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Sample records for drug targeting

  1. GWAS and drug targets

    PubMed Central

    2014-01-01

    Background Genome wide association studies (GWAS) have revealed a large number of links between genome variation and complex disease. Among other benefits, it is expected that these insights will lead to new therapeutic strategies, particularly the identification of new drug targets. In this paper, we evaluate the power of GWAS studies to find drug targets by examining how many existing drug targets have been directly 'rediscovered' by this technique, and the extent to which GWAS results may be leveraged by network information to discover known and new drug targets. Results We find that only a very small fraction of drug targets are directly detected in the relevant GWAS studies. We investigate two possible explanations for this observation. First, we find evidence of negative selection acting on drug target genes as a consequence of strong coupling with the disease phenotype, so reducing the incidence of SNPs linked to the disease. Second, we find that GWAS genes are substantially longer on average than drug targets and than all genes, suggesting there is a length related bias in GWAS results. In spite of the low direct relationship between drug targets and GWAS reported genes, we found these two sets of genes are closely coupled in the human protein network. As a consequence, machine-learning methods are able to recover known drug targets based on network context and the set of GWAS reported genes for the same disease. We show the approach is potentially useful for identifying drug repurposing opportunities. Conclusions Although GWA studies do not directly identify most existing drug targets, there are several reasons to expect that new targets will nevertheless be discovered using these data. Initial results on drug repurposing studies using network analysis are encouraging and suggest directions for future development. PMID:25057111

  2. Targeting drugs to mitochondria.

    PubMed

    Heller, Anne; Brockhoff, Gero; Goepferich, Achim

    2012-09-01

    Mitochondria are of an increasing interest in pharmaceutical and medical research since it has been reported that dysfunction of these organelles contributes to several diseases with a great diversity of clinical appearance. By the fact that mitochondria are located inside the cell and, in turn, origins of mitochondrial diseases or targets of drugs are located inside mitochondria, a drug molecule has to cross several barriers. This is a severe drawback for the selective accumulation of drug molecules in mitochondria. Therefore, targeting strategies such as direct drug modification or encapsulation into nanocarriers have to be applied to achieve an accumulation of drug molecules in these organelles. In this review, it will be demonstrated how properties and dysfunctions of mitochondria are generating a need for the development of mitochondria specific therapies. Furthermore, intracellular targets of mitochondrial diseases, strategies to utilize mitochondrial specificities and targeting approaches will be discussed. Finally, techniques to investigate mitochondrial characteristics and functionality are reviewed.

  3. Old Drug, New Target

    PubMed Central

    Andrews, William J.; Panova, Tatiana; Normand, Christophe; Gadal, Olivier; Tikhonova, Irina G.; Panov, Konstantin I.

    2013-01-01

    Transcription by RNA polymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC50 in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity. We have shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis. PMID:23293027

  4. Drug-Target Kinetics in Drug Discovery.

    PubMed

    Tonge, Peter J

    2017-07-14

    The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

  5. Predicting Drug-Target Interactions Using Drug-Drug Interactions

    PubMed Central

    Kim, Shinhyuk; Jin, Daeyong; Lee, Hyunju

    2013-01-01

    Computational methods for predicting drug-target interactions have become important in drug research because they can help to reduce the time, cost, and failure rates for developing new drugs. Recently, with the accumulation of drug-related data sets related to drug side effects and pharmacological data, it has became possible to predict potential drug-target interactions. In this study, we focus on drug-drug interactions (DDI), their adverse effects () and pharmacological information (), and investigate the relationship among chemical structures, side effects, and DDIs from several data sources. In this study, data from the STITCH database, from drugs.com, and drug-target pairs from ChEMBL and SIDER were first collected. Then, by applying two machine learning approaches, a support vector machine (SVM) and a kernel-based L1-norm regularized logistic regression (KL1LR), we showed that DDI is a promising feature in predicting drug-target interactions. Next, the accuracies of predicting drug-target interactions using DDI were compared to those obtained using the chemical structure and side effects based on the SVM and KL1LR approaches, showing that DDI was the data source contributing the most for predicting drug-target interactions. PMID:24278248

  6. Development of Bone Targeting Drugs

    PubMed Central

    Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

    2017-01-01

    The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

  7. Multidrug transporters as drug targets.

    PubMed

    Liang, X-J; Aszalos, A

    2006-08-01

    Transport molecules can significantly affect the pharmacodynamics and pharmacokinetics of drugs. An important transport molecule, the 170 kDa P-glycoprotein (Pgp), is constitutively expressed at several organ sites in the human body. Pgp is expressed at the blood-brain barrier, in the kidneys, liver, intestines and in certain T cells. Other transporters such as the multidrug resistance protein 1 (MRP1) and MRP2 also contribute to drug distribution in the human body, although to a lesser extent than Pgp. These three transporters, and especially Pgp, are often targets of drugs. Pgp can be an intentional or unintentional target. It is directly targeted when one wants to block its function by a modifier drug so that another drug, also a substrate of Pgp, can penetrate the cell membrane, which would otherwise be impermeable. Unintentional targeting occurs when several drugs are administered to a patient and as a consequence, the physiological function of Pgp is blocked at different organ sites. Like Pgp, MRP1 also has the capacity to mediate transport of many drugs and other compounds. MRP1 has a protective role in preventing accumulation of toxic compounds and drugs in epithelial tissue covering the choroid plexus/cerebrospinal fluid compartment, oral epithelium, sertoli cells, intesticular tubules and urinary collecting duct cells. MRP2 primarily transports weakly basic drugs and bilirubin from the liver to bile. Most compounds that efficiently block Pgp have only low affinity for MRP1 and MRP2. There are only a few effective and specific MRP inhibitors available. Drug targeting of these transporters may play a role in cancer chemotherapy and in the pharmacokinetics of substrate drugs.

  8. Ligand-Targeted Drug Delivery.

    PubMed

    Srinivasarao, Madduri; Low, Philip S

    2017-09-12

    Safety and efficacy constitute the major criteria governing regulatory approval of any new drug. The best method to maximize safety and efficacy is to deliver a proven therapeutic agent with a targeting ligand that exhibits little affinity for healthy cells but high affinity for pathologic cells. The probability of regulatory approval can conceivably be further enhanced by exploiting the same targeting ligand, conjugated to an imaging agent, to select patients whose diseased tissues display sufficient targeted receptors for therapeutic efficacy. The focus of this Review is to summarize criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity. Because most LTDs are composed of a targeting ligand (e.g., organic molecule, aptamer, protein scaffold, or antibody), spacer, cleavable linker, and therapeutic warhead, criteria for successful design of each component will be described. Moreover, because obstacles to successful drug design can differ among human pathologies, limitations to drug delivery imposed by the unique characteristics of different diseases will be considered. With the explosion of genomic and transcriptomic data providing an ever-expanding selection of disease-specific targets, and with tools for high-throughput chemistry offering an escalating diversity of warheads, opportunities for innovating safe and effective LTDs has never been greater.

  9. Chloride channels as drug targets

    PubMed Central

    Verkman, Alan S.; Galietta, Luis J. V.

    2013-01-01

    Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery. PMID:19153558

  10. Hyperthermia-induced drug targeting.

    PubMed

    May, Jonathan P; Li, Shyh-Dar

    2013-04-01

    Specific delivery of a drug to a target site is a major goal of drug delivery research. Using temperature-sensitive liposomes (TSLs) is one way to achieve this; the liposome acts as a protective carrier, allowing increased drug to flow through the bloodstream by minimizing clearance and non-specific uptake. On reaching microvessels within a heated tumor, the drug is released and quickly penetrates. A major advance in the field is ThermoDox® (Celsion), demonstrating significant improvements to the drug release rates and drug uptake in heated tumors (∼ 41°C). Most recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been combined with TSL drug delivery to provide localized chemotherapy with simultaneous quantification of drug release within the tumor. In this article the field of hyperthermia-induced drug delivery is discussed, with an emphasis on the development of TSLs and their combination with hyperthermia (both mild and ablative) in cancer therapy. State-of-the-art image-guided heating technologies used with this combination strategy will also be presented, with examples of real-time monitoring of drug delivery and prediction of efficacy. The specific delivery of drugs by combining hyperthermia with TSLs is showing great promise in the clinic and its potential will be even greater as the use of image-guided focused ultrasound becomes more widespread - a technique capable of penetrating deep within the body to heat a specific area with improved control. In conjunction with this, it is anticipated that multifunctional TSLs will be a major topic of study in this field.

  11. DNA Methylation-Targeted Drugs.

    PubMed

    Da Costa, Elodie M; McInnes, Gabrielle; Beaudry, Annie; Raynal, Noël J-M

    Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficient in monotherapy against hematologic malignancies, the potential of DNA methyltransferase inhibitors to synergize with small molecules targeting chromatin or immunotherapy will provide additional opportunities for their future clinical application against leukemia and solid tumors.

  12. Target Oriented Drugs against Leishmania

    DTIC Science & Technology

    1981-10-26

    leishmanlal excreted factor (EF) antibody in rabbit sera was developed. The assay, using Leishmania trop ica and Leishmania donovani promastigote EF...tropica LRC L137 L52 Leishmaniia donovani LRC L52 These strains were obtained from the WHO Leishmania Peference Centre collection maintained in the...FO 0 AD M FINAL REPORT0 (N TARGET ORIENTED DRUGS AGAINST LEISHMANIA I URI ZEHAVI, Ph.D. and JOSEPH EL-ON, Ph.D. Supported by U.S. ARMY MEDICAL

  13. Homodimeric enzymes as drug targets.

    PubMed

    Cardinale, D; Salo-Ahen, O M H; Ferrari, S; Ponterini, G; Cruciani, G; Carosati, E; Tochowicz, A M; Mangani, S; Wade, R C; Costi, M P

    2010-01-01

    Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homo- and/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb.org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.

  14. Other targeted drugs in melanoma

    PubMed Central

    Rodón, Jordi; Karachaliou, Niki; Sánchez, Jesús; Santarpia, Mariacarmela; Viteri, Santiago; Pilotto, Sara; Teixidó, Cristina; Riso, Aldo; Rosell, Rafael

    2015-01-01

    Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are “targeted” to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other “druggable” kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials. PMID:26605312

  15. Drug targeting through pilosebaceous route.

    PubMed

    Chourasia, Rashmi; Jain, Sanjay K

    2009-10-01

    Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery.

  16. Properties of Protein Drug Target Classes

    PubMed Central

    Bull, Simon C.; Doig, Andrew J.

    2015-01-01

    Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID

  17. Drug target identification in protozoan parasites

    PubMed Central

    Müller, Joachim; Hemphill, Andrew

    2016-01-01

    Introduction Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Areas covered Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Expert opinion Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID:27238605

  18. Drug target identification in protozoan parasites.

    PubMed

    Müller, Joachim; Hemphill, Andrew

    2016-08-01

    Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

  19. Automated High Throughput Drug Target Crystallography

    SciTech Connect

    Rupp, B

    2005-02-18

    The molecular structures of drug target proteins and receptors form the basis for 'rational' or structure guided drug design. The majority of target structures are experimentally determined by protein X-ray crystallography, which as evolved into a highly automated, high throughput drug discovery and screening tool. Process automation has accelerated tasks from parallel protein expression, fully automated crystallization, and rapid data collection to highly efficient structure determination methods. A thoroughly designed automation technology platform supported by a powerful informatics infrastructure forms the basis for optimal workflow implementation and the data mining and analysis tools to generate new leads from experimental protein drug target structures.

  20. Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

    PubMed

    Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

    2017-01-20

    Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

  1. Therapeutic drug monitoring of targeted anticancer therapy.

    PubMed

    Decosterd, Laurent A; Widmer, Nicolas; Zaman, Khalil; Cardoso, Evelina; Buclin, Thierry; Csajka, Chantal

    2015-01-01

    New oral targeted anticancer therapies are revolutionizing cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, drug resistance, persistence of cancer stem cells, and adverse drug effects still limit their ability to stabilize or cure malignant diseases in the long term. Response to targeted anticancer therapy is influenced by tumor genetics and by variability in drug concentrations. However, despite a significant inter-patient pharmacokinetic variability, targeted anticancer drugs are essentially licensed at fixed doses. Their therapeutic use could however be optimized by individualization of their dosage, based on blood concentration measurements via the therapeutic drug monitoring (TDM). TDM can increase the probability of therapeutic responses to targeted anticancer therapies, and would help minimize the risk of major adverse reactions.

  2. Tumor targeting using liposomal antineoplastic drugs

    PubMed Central

    Huwyler, Jörg; Drewe, Jürgen; Krähenbühl, Stephan

    2008-01-01

    During the last years, liposomes (microparticulate phospholipid vesicles) have been used with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of application include lipid-based formulations to enhance the solubility of poorly soluble antitumor drugs, the use of pegylated liposomes for passive targeting of solid tumors as well as vector-conjugated liposomal carriers for active targeting of tumor tissue. Such formulation and drug targeting strategies enhance the effectiveness of anticancer chemotherapy and reduce at the same time the risk of toxic side-effects. The present article reviews the principles of different liposomal technologies and discusses current trends in this field of research. PMID:18488413

  3. Novel drugs targeting sphingolipid metabolism.

    PubMed

    Bhabak, Krishna P; Arenz, Christoph

    2013-01-01

    While the evidence for an involvement of sphingolipids (SLs) in a variety of diseases is rapidly increasing, the development of sphingolipid-related drugs is still in its infancy. In fact, the recently FDA-approved fingolimod or FTY-720 (see chapter by J. Pfeilschifter for more information) is the first drug on the market to interfere with sphingolipid signaling. The reasons for this lagging are manifold and within this chapter we try to name some of them. Ceramide is in the center of sphingolipid metabolism. We describe the most important and most recent inhibitors for enzymes controlling cellular ceramide levels.

  4. Targeted drugs and nanomedicine: present and future.

    PubMed

    Debbage, Paul

    2009-01-01

    Packaging small-molecule drugs into nanoparticles improves their bio-availability, bio-compatibility and safety profiles. Multifunctional particles carrying large drug payloads for targeted transport, immune evasion and favourable drug release kinetics at the target site, require a certain minimum size usually 30-300 nm diameter, so are nanoparticles. Targeting particles to a disease site can signal the presence of the disease site, block a function there, or deliver a drug to it. Targeted nanocarriers must navigate through blood-tissue barriers, varying in strength between organs and highest in the brain, to reach target cells. They must enter target cells to contact cytoplasmic targets; specific endocytotic and transcytotic transport mechanisms can be used as trojan horses to ferry nanoparticles across cellular barriers. Specific ligands to cell surface receptors, antibodies and antibody fragments, and aptamers can all access such transport mechanisms to ferry nanoparticles to their targets. The pharmacokinetics and pharmacodynamics of the targeted drug-bearing particle depend critically on particle size, chemistry, surface charge and other parameters. Particle types for targeting include liposomes, polymer and protein nanoparticles, dendrimers, carbon-based nanoparticles e.g. fullerenes, and others. Immunotargeting by use of monoclonal antibodies, chimeric antibodies and humanized antibodies has now reached the stage of clinical application. High-quality targeting groups are emerging: antibody engineering enables generation of human/like antibody (fragments) and facilitates the search for clinically relevant biomarkers; conjugation of nanocarriers to specific ligands and to aptamers enables specific targeting with improved clinical efficacy. Future developments depend on identification of clinically relevant targets and on raising targeting efficiency of the multifunctional nanocarriers.

  5. Predicting new molecular targets for known drugs

    PubMed Central

    Keiser, Michael J.; Setola, Vincent; Irwin, John J.; Laggner, Christian; Abbas, Atheir; Hufeisen, Sandra J.; Jensen, Niels H.; Kuijer, Michael B.; Matos, Roberto C.; Tran, Thuy B.; Whaley, Ryan; Glennon, Richard A.; Hert, Jérôme; Thomas, Kelan L.H.; Edwards, Douglas D.; Shoichet, Brian K.; Roth, Bryan L.

    2009-01-01

    Whereas drugs are intended to be selective, at least some bind to several physiologic targets, explaining both side effects and efficacy. As many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here, we compared 3,665 FDA-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-HT transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (< 100 nM). The physiological relevance of one such, the drug DMT on serotonergic receptors, was confirmed in a knock-out mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs. PMID:19881490

  6. Target assessment for antiparasitic drug discovery.

    PubMed

    Frearson, Julie A; Wyatt, Paul G; Gilbert, Ian H; Fairlamb, Alan H

    2007-12-01

    Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising the chances of success. Here, we describe criteria used in our drug discovery unit for target assessment and introduce the 'traffic-light' system as a prioritisation and management tool. We hope this brief review will stimulate basic scientists to acquire additional information necessary for drug discovery.

  7. Drug targeting using solid lipid nanoparticles.

    PubMed

    Rostami, Elham; Kashanian, Soheila; Azandaryani, Abbas H; Faramarzi, Hossain; Dolatabadi, Jafar Ezzati Nazhad; Omidfar, Kobra

    2014-07-01

    The present review aims to show the features of solid lipid nanoparticles (SLNs) which are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery and research. Because of some unique features of SLNs such as their unique size dependent properties it offers possibility to develop new therapeutics. A common denominator of all these SLN-based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. SLNs are capable to incorporate drugs into nanocarriers which lead to a new prototype in drug delivery which maybe used for drug targeting. Hence solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence attracted wide attention of researchers. This review presents a broad treatment of targeted solid lipid nanoparticles discussing their types such as antibody SLN, magnetic SLN, pH sensitive SLN and cationic SLN.

  8. Multi-Target Drugs for Neglected Diseases.

    PubMed

    Scotti, Luciana; Filho, Francisco J B M; de Moura, Ricardo O; Ribeiro, Frederico F; Ishiki, Hamilton; da Silva, Marcelo S; Filho, José M B; Scotti, Marcus T

    2016-05-30

    Diseases perceived as neglected tropical infections are generally caused by parasites which reach poor, underserved populations (primarily infrastructure), cause serious damage to health, and many deaths. AIDS and tuberculosis, (although not classified as neglected by WHO), are discriminated against infections which cause great social damage. The drugs currently used to treat these diseases do not have the desired effectiveness, enable the emergence of resistant strains, and in most cases are difficult to obtain. Few pharmaceutical companies are investing in new drug research for neglected diseases, for lack of financial return. This review reports the major neglected diseases, AIDS, tuberculosis, their targets, and research on multi-target drugs. The studies for new drugs against these infections involve in silico methods, synthesis, structural determinations, analytical analysis and other experimental assays. A new single compound, forecasting possible pharmacodynamic and pharmacokinetic interactions becomes a simpler process; it is also believed that these drugs are safer and more efficient, since they act with synergism on different targets. It occurs but the emergence of new resistant strains and side effects. Multi-target drugs represent a new alternative to find new lead compounds. A ligand that targets two or more receivers may be seen as a potential drug, combating infection by different routes.

  9. Atypical GTPases as drug targets.

    PubMed

    Soundararajan, Meera; Eswaran, Jeyanthy

    2012-01-01

    The Ras GTPases are the founding members of large Ras superfamily, which constitutes more than 150 of these important class of enzymes. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. There are a number of GTPases that have been identified recently, which do not confine to this prototype termed as "atypical GTPases" but have proved to play a remarkable role in vital cellular functions. In this review, we provide an overview of the crucial physiological functions mediated by RGK and Centaurin class of multi domain atypical GTPases. Moreover, the recently available atypical GTPase structures of the two families, regulation, physiological functions and their critical roles in various diseases will be discussed. In summary, this review will highlight the emerging atypical GTPase family which allows us to understand novel regulatory mechanisms and thus providing new avenues for drug discovery programs.

  10. Nanogel Carrier Design for Targeted Drug Delivery

    PubMed Central

    Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

  11. Targeted Delivery of Protein Drugs by Nanocarriers

    PubMed Central

    Solaro, Roberto; Chiellini, Federica; Battisti, Antonella

    2010-01-01

    Recent advances in biotechnology demonstrate that peptides and proteins are the basis of a new generation of drugs. However, the transportation of protein drugs in the body is limited by their high molecular weight, which prevents the crossing of tissue barriers, and by their short lifetime due to immuno response and enzymatic degradation. Moreover, the ability to selectively deliver drugs to target organs, tissues or cells is a major challenge in the treatment of several human diseases, including cancer. Indeed, targeted delivery can be much more efficient than systemic application, while improving bioavailability and limiting undesirable side effects. This review describes how the use of targeted nanocarriers such as nanoparticles and liposomes can improve the pharmacokinetic properties of protein drugs, thus increasing their safety and maximizing the therapeutic effect.

  12. Giardiasis, drug resistance, and new target discovery.

    PubMed

    Tian, Hai-Feng; Chen, Bing; Wen, Jian-Fan

    2010-08-01

    Giardiasis is a worldwide parasitic disease caused by the protozoan Giardia lamblia in humans and other animals, especially live stocks. Here, we briefly review the current state of therapeutic availability for giardiasis, including chemical drugs and vaccines, and the dilemma in the prevention and treatment of this disease, including the emergence of drug resistance and the shortage of vaccine (especially for humans). Future efforts and progress in controlling giardiasis are expected in three aspects: clarification of the drug resistance mechanisms, development of efficient vaccines, and identification of more targets for new drugs and vaccines.

  13. Fluid mechanics aspects of magnetic drug targeting.

    PubMed

    Odenbach, Stefan

    2015-10-01

    Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load.

  14. Biocomputational strategies for microbial drug target identification.

    PubMed

    Sakharkar, Kishore R; Sakharkar, Meena K; Chow, Vincent T K

    2008-01-01

    The complete genome sequences of about 300 bacteria (mostly pathogenic) have been determined, and many more such projects are currently in progress. The detection of bacterial genes that are non-homologous to human genes and are essential for the survival of the pathogen represent a promising means of identifying novel drug targets. We present a subtractive genomics approach for the identification of putative drug targets in microbial genomes and demonstrate its execution using Pseudomonas aeruginosa as an example. The resultant analyses are in good agreement with the results of systematic gene deletion experiments. This strategy enables rapid potential drug target identification, thereby greatly facilitating the search for new antibiotics. It should be recognized that there are limitations to this computational approach for drug target identification. Distant gene relationships may be missed since the alignment scores are likely to have low statistical significance. In conclusion, the results of such a strategy underscore the utility of large genomic databases for in silico systematic drug target identification in the post-genomic era.

  15. Injected nanocrystals for targeted drug delivery

    PubMed Central

    Lu, Yi; Li, Ye; Wu, Wei

    2016-01-01

    Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies. PMID:27006893

  16. Protein-protein interactions as drug targets.

    PubMed

    Skwarczynska, Malgorzata; Ottmann, Christian

    2015-01-01

    Modulation of protein-protein interactions (PPIs) is becoming increasingly important in drug discovery and chemical biology. While a few years ago this 'target class' was deemed to be largely undruggable an impressing number of publications and success stories now show that targeting PPIs with small, drug-like molecules indeed is a feasible approach. Here, we summarize the current state of small-molecule inhibition and stabilization of PPIs and review the active molecules from a structural and medicinal chemistry angle, especially focusing on the key examples of iNOS, LFA-1 and 14-3-3.

  17. Nanoparticles for intracellular-targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Paulo, Cristiana S. O.; Pires das Neves, Ricardo; Ferreira, Lino S.

    2011-12-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  18. Open Challenges in Magnetic Drug Targeting

    PubMed Central

    Kulkarni, Sandip; Nacev, Aleksander; Muro, Silvia; Stepanov, Pavel Y.; Weinberg, Irving N.

    2014-01-01

    The principle of magnetic drug targeting, wherein therapy is attached to magnetically responsive carriers and magnetic fields are used to direct that therapy to disease locations, has been around for nearly two decades. Yet our ability to safely and effectively direct therapy to where it needs to go, for instance to deep tissue targets, remains limited. To date, magnetic targeting methods have not yet passed regulatory approval or reached clinical use. Below we outline key challenges to magnetic targeting, which include designing and selecting magnetic carriers for specific clinical indications, safely and effectively reaching targets behind tissue and anatomical barriers, real-time carrier imaging, and magnet design and control for deep and precise targeting. Addressing these challenges will require interactions across disciplines. Nanofabricators and chemists should work with biologists, mathematicians and engineers to better understand how carriers move through live tissues and how to optimize carrier and magnet designs to better direct therapy to disease targets. Clinicians should be involved early on and throughout the whole process to ensure the methods that are being developed meet a compelling clinical need and will be practical in a clinical setting. Our hope is that highlighting these challenges will help researchers translate magnetic drug targeting from a novel concept to a clinically-available treatment that can put therapy where it needs to go in human patients. PMID:25377422

  19. Analysis of adverse drug reactions using drug and drug target interactions and graph-based methods.

    PubMed

    Lin, Shih-Fang; Xiao, Ke-Ting; Huang, Yu-Ting; Chiu, Chung-Cheng; Soo, Von-Wun

    2010-01-01

    The purpose of this study was to integrate knowledge about drugs, drug targets, and topological methods. The goals were to build a system facilitating the study of adverse drug events, to make it easier to find possible explanations, and to group similar drug-drug interaction cases in the adverse drug reaction reports from the US Food and Drug Administration (FDA). We developed a system that analyses adverse drug reaction (ADR) cases reported by the FDA. The system contains four modules. First, we integrate drug and drug target databases that provide information related to adverse drug reactions. Second, we classify drug and drug targets according to anatomical therapeutic chemical classification (ATC) and drug target ontology (DTO). Third, we build drug target networks based on drug and drug target databases. Finally, we apply topological analysis to reveal drug interaction complexity for each ADR case reported by the FDA. We picked 1952 ADR cases from the years 2005-2006. Our dataset consisted of 1952 cases, of which 1471 cases involved ADR targets, 845 cases involved absorption, distribution, metabolism, and excretion (ADME) targets, and 507 cases involved some drugs acting on the same targets, namely, common targets (CTs). We then investigated the cases involving ADR targets, ADME targets, and CTs using the ATC system and DTO. In the cases that led to death, the average number of common targets (NCTs) was 0.879 and the average of average clustering coefficient (ACC) was 0.067. In cases that did not lead to death, the average NCTs was 0.551, and the average of ACC was 0.039. We implemented a system that can find possible explanations and cluster similar ADR cases reported by the FDA. We found that the average of ACC and the average NCTs in cases leading to death are higher than in cases not leading to death, suggesting that the interactions in cases leading to death are generally more complicated than in cases not leading to death. This indicates that our system

  20. Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs.

    PubMed

    Tao, Lin; Zhu, Feng; Xu, Feng; Chen, Zhe; Jiang, Yu Yang; Chen, Yu Zong

    2015-12-01

    Recent investigations have suggested that anticancer therapeutics may be enhanced by co-targeting the primary anticancer target and the corresponding drug escape pathways. Whether this strategy confers statistically significant clinical advantage has not been systematically investigated. This question was probed by the evaluation of the clinical status and the multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs with particular focus on those co-targeting EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase, and some of the 14, 7, 13, 20, 6, 5, 7, 2, 4 and 10 cancer drug escape pathways respectively. Most of the approved (73.9%) and phase III (75.0%), the majority of the Phase II (62.8%) and I (53.6%), and the minority of the discontinued (35.3%) multi-target drugs were found to co-target cancer drug escape pathways. This suggests that co-targeting anticancer targets and drug escape pathways confer significant clinical advantage and such strategy can be more extensively explored. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Chemical signatures and new drug targets for gametocytocidal drug development

    NASA Astrophysics Data System (ADS)

    Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei

    2014-01-01

    Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

  2. Bacterial proteases, untapped antimicrobial drug targets.

    PubMed

    Culp, Elizabeth; Wright, Gerard D

    2017-04-01

    Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

  3. Amphotericin B formulations and drug targeting.

    PubMed

    Torrado, J J; Espada, R; Ballesteros, M P; Torrado-Santiago, S

    2008-07-01

    Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome, Abelcet, and Amphotec) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations.

  4. Targeted proteins for diabetes drug design

    NASA Astrophysics Data System (ADS)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  5. UniDrug-Target: A Computational Tool to Identify Unique Drug Targets in Pathogenic Bacteria

    PubMed Central

    Chanumolu, Sree Krishna; Rout, Chittaranjan; Chauhan, Rajinder S.

    2012-01-01

    Background Targeting conserved proteins of bacteria through antibacterial medications has resulted in both the development of resistant strains and changes to human health by destroying beneficial microbes which eventually become breeding grounds for the evolution of resistances. Despite the availability of more than 800 genomes sequences, 430 pathways, 4743 enzymes, 9257 metabolic reactions and protein (three-dimensional) 3D structures in bacteria, no pathogen-specific computational drug target identification tool has been developed. Methods A web server, UniDrug-Target, which combines bacterial biological information and computational methods to stringently identify pathogen-specific proteins as drug targets, has been designed. Besides predicting pathogen-specific proteins essentiality, chokepoint property, etc., three new algorithms were developed and implemented by using protein sequences, domains, structures, and metabolic reactions for construction of partial metabolic networks (PMNs), determination of conservation in critical residues, and variation analysis of residues forming similar cavities in proteins sequences. First, PMNs are constructed to determine the extent of disturbances in metabolite production by targeting a protein as drug target. Conservation of pathogen-specific protein's critical residues involved in cavity formation and biological function determined at domain-level with low-matching sequences. Last, variation analysis of residues forming similar cavities in proteins sequences from pathogenic versus non-pathogenic bacteria and humans is performed. Results The server is capable of predicting drug targets for any sequenced pathogenic bacteria having fasta sequences and annotated information. The utility of UniDrug-Target server was demonstrated for Mycobacterium tuberculosis (H37Rv). The UniDrug-Target identified 265 mycobacteria pathogen-specific proteins, including 17 essential proteins which can be potential drug targets. Conclusions

  6. Putative Drugs and Targets for Bipolar Disorder

    PubMed Central

    Zarate, Carlos A.; Manji, Husseini K.

    2009-01-01

    Current pharmacotherapy for bipolar disorder (BPD) is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment and psychosocial disability. Creating novel therapeutics for BPD is urgently needed. Promising drug targets and compounds for BPD worthy of further study involve the following systems: purinergic, dynorphin opioid neuropeptide, cholinergic (muscarinic and nicotinic), melatonin and serotonin (5-HT2C receptor), glutamatergic, hypothalamic-pituitary adrenal (HPA) axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, arachidonic acid cascade. PMID:18704977

  7. Histone as future drug target for malaria.

    PubMed

    Rawat, D S; Lumb, V; Sharma, Y D; Pasha, S T; Singh, G

    2007-06-01

    Malaria continues to be a major cause of mortality and morbidity in tropical countries and affecting around 100 countries of the world. As per WHO estimates, 300-500 million are being infected and 1-3 million deaths annually due to malaria. With the emerging knowledge about genome sequence of all the three counterparts involved in the disease of malaria, the parasite Plasmodium, vector Anopheles and host Homo sapien have helped the scientists to understand interactions between them. Simultaneous advancement in technology further improves the prospects to discover new targets for vaccines and drugs. Though the malaria vaccine is still far away in this situation there is need to develop a potent and affordable drug(s). Histones are the key protein of chromatin and play an important role in DNA packaging, replication and gene expression. They also show frequent post-translation modifications. The specific combinations of these posttranslational modifications are thought to alter chromatin structure by forming epigenetic bar codes that specify either transient or heritable patterns of genome function. Chromatin regulators and upstream pathways are therefore seen as promising targets for development of therapeutic drugs.

  8. Targets for anti-metastatic drug development.

    PubMed

    Stock, Anna-Maria; Troost, Gabriele; Niggemann, Bernd; Zänker, Kurt S; Entschladen, Frank

    2013-01-01

    With a constant focus on the primary tumor, the current approaches in drug development in oncology yield dismal results. However over 90 percent of cancer deaths today are due to metastasis formation and yet there is no anti-metastatic drug on the market. Tumor cell migration is the essential prerequisite for invasion and metastasis formation. It is regulated by signal substances in terms of the grade of activity and in terms of direction (chemotaxis). The latter is important for the organotropism, the localization of metastasis in certain organs. Ligands to G protein-coupled receptors, mainly chemokines and neurotransmitters, as well as ligands to receptor kinases, mainly cytokines and growth factors, form the most important group of such regulators. We provide an overview of currently available agonists and antagonists to these receptors, which have a potential as anti-metastatic targets. Moreover we provide with the example of beta-blockers, how established drugs in other indications are possibly effective and can be co-opted as such anti-metastatics. The increasing knowledge of such regulators opens new opportunities to target cancer spreading and may put forth the development of antimetastatic drugs for oncological therapy.

  9. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  10. Endocrine receptors as targets for new drugs.

    PubMed

    Altman, Jennifer

    2006-01-01

    Increasingly detailed knowledge of cellular signalling pathways is providing a sound basis for the development of specific drugs aimed at selected components of the pathways. Many of these targets are receptors and the multitude of hormone receptors makes endocrine functions a rich proving ground for this research. This article reviews a recent meeting (Insights into Receptor Function and New Drug Development Targets; 5th Endocrinology Colloquium of the Fondation Ipsen, Paris, December 5, 2005) where progress in defining suitable targets for drug therapies in the endocrine system and in designing drugs for some of these targets was discussed. Although the family of G-protein-coupled receptors, ubiquitous in the endocrine system, was the central focus, comparisons with other receptor families were made. Many mutations affecting genes coding for receptors or other components of signalling pathways have been found in a wide range of endocrine disorders including obesity, parathyroid malfunction, disorders involving thyroid-stimulating hormone and follicle-stimulating hormone, and tumours in the anterior pituitary, as well as in many types of cancer. These are being used to dissect the normal control mechanisms as well as to provide information for the development of selective drugs. Recently identified mutations that affect the intracellular traffic in newly synthesised receptors open up possibilities of another dimension of cellular regulation of signalling. Both the discovery of hormones such as apelin and its pairing with an 'orphan' receptor, and the unexpected action of a drug against cannabinoid receptors point to further levels of complexity in cardiovascular regulation. Deeper understanding of the evolution of receptor families and of the molecular mechanisms of signal transduction is enabling the design of highly specific agonists and antagonists. Pharmacological intervention is not limited to the ligand-receptor interaction but can extend to inhibition of

  11. Stapled peptides for intracellular drug targets.

    PubMed

    Verdine, Gregory L; Hilinski, Gerard J

    2012-01-01

    Proteins that engage in intracellular interactions with other proteins are widely considered among the most biologically appealing yet chemically intractable targets for drug discovery. The critical interaction surfaces of these proteins typically lack the deep hydrophobic involutions that enable potent, selective targeting by small organic molecules, and their localization within the cell puts them beyond the reach of protein therapeutics. Considerable interest has therefore arisen in next-generation targeting molecules that combine the broad target recognition capabilities of protein therapeutics with the robust cell-penetrating ability of small molecules. One type that has shown promise in early-stage studies is hydrocarbon-stapled α-helical peptides, a novel class of synthetic miniproteins locked into their bioactive α-helical fold through the site-specific introduction of a chemical brace, an all-hydrocarbon staple. Stapling can greatly improve the pharmacologic performance of peptides, increasing their target affinity, proteolytic resistance, and serum half-life while conferring on them high levels of cell penetration through endocytic vesicle trafficking. Here, we discuss considerations crucial to the successful design and evaluation of potent stapled peptide interactions, our intention being to facilitate the broad application of this technology to intractable targets of both basic biologic interest and potential therapeutic value.

  12. Malaria heat shock proteins: drug targets that chaperone other drug targets.

    PubMed

    Pesce, E-R; Cockburn, I L; Goble, J L; Stephens, L L; Blatch, G L

    2010-06-01

    Ongoing research into the chaperone systems of malaria parasites, and particularly of Plasmodium falciparum, suggests that heat shock proteins (Hsps) could potentially be an excellent class of drug targets. The P. falciparum genome encodes a vast range and large number of chaperones, including 43 Hsp40, six Hsp70, and three Hsp90 proteins (PfHsp40s, PfHsp70s and PfHsp90s), which are involved in a number of fundamental cellular processes including protein folding and assembly, protein translocation, signal transduction and the cellular stress response. Despite the fact that Hsps are relatively conserved across different species, PfHsps do exhibit a considerable number of unique structural and functional features. One PfHsp90 is thought to be sufficiently different to human Hsp90 to allow for selective targeting. PfHsp70s could potentially be used as drug targets in two ways: either by the specific inhibition of Hsp70s by small molecule modulators, as well as disruption of the interactions between Hsp70s and co-chaperones such as the Hsp70/Hsp90 organising protein (Hop) and Hsp40s. Of the many PfHsp40s present on the parasite, there are certain unique or essential members which are considered to have good potential as drug targets. This review critically evaluates the potential of Hsps as malaria drug targets, as well as the use of chaperones as aids in the heterologous expression of other potential malarial drug targets.

  13. Parasitic diarrheal disease: drug development and targets

    PubMed Central

    Azam, Amir; Peerzada, Mudasir N.; Ahmad, Kamal

    2015-01-01

    Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active anti-parasitic agents. PMID:26617574

  14. New drugs and treatment targets in psoriasis.

    PubMed

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-02-01

    In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic in the next years. Biologics are costly, require injections, and some patients experience tacaphylaxis, thus, the development of orally available, small-molecule inhibitors is desirable. Among small-molecules under investigation are A3 adenosine receptor agonists, Janus kinase inhibitors, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools.

  15. DRUG TARGET PREDICTIONS BASED ON HETEROGENEOUS GRAPH INFERENCE

    PubMed Central

    Wang, Wenhui; Yang, Sen; Li, JING

    2013-01-01

    A key issue in drug development is to understand the hidden relationships among drugs and targets. Computational methods for novel drug target predictions can greatly reduce time and costs compared with experimental methods. In this paper, we propose a network based computational approach for novel drug and target association predictions. More specifically, a heterogeneous drug-target graph, which incorporates known drug-target interactions as well as drug-drug and target-target similarities, is first constructed. Based on this graph, a novel graph-based inference method is introduced. Compared with two state-of-the-art methods, large-scale cross-validation results indicate that the proposed method can greatly improve novel target predictions. PMID:23424111

  16. GABA transporters as targets for new drugs.

    PubMed

    Sałat, Kinga; Kulig, Katarzyna

    2011-02-01

    GABA, the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. The identification and subsequent development of GABA-transport inhibitors has shown the important role that GABA transporters play in the control of the CNS. To date, four GABA transporters have been cloned (GAT1-4). Compounds that inhibit GABA uptake are targets for epilepsy treatment. Currently, they are also being investigated for other possible indications such as the treatment of psychosis, general anxiety and sleep disorders, drug addiction, acute and chronic pain. These and other issues are discussed in this article.

  17. Drug Targets in Mycobacterial Sulfur Metabolism

    PubMed Central

    Bhave, Devayani P.; Muse, Wilson B.; Carroll, Kate S.

    2011-01-01

    The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress in the development of inhibitors of sulfur metabolism enzymes. PMID:17970225

  18. P2X Receptors as Drug Targets

    PubMed Central

    Jarvis, Michael F.

    2013-01-01

    The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets. PMID:23253448

  19. NSAIDs: Old Drugs Reveal New Anticancer Targets.

    PubMed

    Piazza, Gary A; Keeton, Adam B; Tinsley, Heather N; Whitt, Jason D; Gary, Bernard D; Mathew, Bini; Singh, Raj; Grizzle, William E; Reynolds, Robert C

    2010-05-25

    There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based on in silico modeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention.

  20. Magnetic Drug Targeting in Arterial Flows

    NASA Astrophysics Data System (ADS)

    Williams, Alicia; Puri, Ishwar; Vlachos, Pavlos

    2006-11-01

    Magnetic Drug Targeting (MDT) is a promising technique to effectively deliver medicinal drugs via functionalized magnetic particles to target sites during the treatment of diseases. In this paper we investigate the interaction of coronary and pulsatile flows laden with superparamagnetic microparticles in a vessel under the influence of a magnetic field induced by a 1 Tesla permanent magnet. Coronary and peripheral pulsatile flows were examined across a range of conditions that are representative of those found within the cardiovascular system. The flow in the model was measured using TRDPIV (Time Resolved Digital Particle Image Velocimetry) and data was acquired with sampling up to 1 kHz. The data obtained from the experiment indicates that for the range of flows studied, the behavior of the ferrofluid mass is physically abundant. The ferrofluid mass deforms in response to the pulsatility of the flow, generating wavy structures that ultimately shed portions of the ferrofluid downstream in a fashion similar to a Kelvin-Helmholtz shear layer. This experiment is the first to address the fluid dynamics of the interactions between the flow and the ferrofluid mass over the range of biological conditions.

  1. Zika Virus Protease: An Antiviral Drug Target.

    PubMed

    Kang, CongBao; Keller, Thomas H; Luo, Dahai

    2017-10-01

    The recent outbreak of Zika virus (ZIKV) infection has caused global concern due to its link to severe damage to the brain development of foetuses and neuronal complications in adult patients. A worldwide research effort has been undertaken to identify effective and safe treatment and vaccination options. Among the proposed viral and host components, the viral NS2B-NS3 protease represents an attractive drug target due to its essential role in the virus life cycle. Here, we outline recent progress in studies on the Zika protease. Biochemical, biophysical, and structural studies on different protease constructs provide new insight into the structure and activity of the protease. The unlinked construct displays higher enzymatic activity and better mimics the native state of the enzyme and therefore is better suited for drug discovery. Furthermore, the structure of the free enzyme adopts a closed conformation and a preformed active site. The availability of a lead fragment hit and peptide inhibitors, as well as the attainability of soakable crystals, suggest that the unlinked construct is a promising tool for drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Hsp70 Protein Complexes as Drug Targets

    PubMed Central

    Assimon, Victoria A.; Gillies, Anne T.; Rauch, Jennifer N.; Gestwicki, Jason E.

    2013-01-01

    Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70’s interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, such as pro-folding, pro-degradation and pro-trafficking. Thus, a promising strategy may be to block protein-protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to those goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology. PMID:22920901

  3. Hsp70 protein complexes as drug targets.

    PubMed

    Assimon, Victoria A; Gillies, Anne T; Rauch, Jennifer N; Gestwicki, Jason E

    2013-01-01

    Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70's interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, including roles in pro-folding, pro-degradation and pro-trafficking pathways. Thus, a promising strategy may be to block protein- protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to these goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology.

  4. Drug Target Protein-Protein Interaction Networks: A Systematic Perspective.

    PubMed

    Feng, Yanghe; Wang, Qi; Wang, Tengjiao

    2017-01-01

    The identification and validation of drug targets are crucial in biomedical research and many studies have been conducted on analyzing drug target features for getting a better understanding on principles of their mechanisms. But most of them are based on either strong biological hypotheses or the chemical and physical properties of those targets separately. In this paper, we investigated three main ways to understand the functional biomolecules based on the topological features of drug targets. There are no significant differences between targets and common proteins in the protein-protein interactions network, indicating the drug targets are neither hub proteins which are dominant nor the bridge proteins. According to some special topological structures of the drug targets, there are significant differences between known targets and other proteins. Furthermore, the drug targets mainly belong to three typical communities based on their modularity. These topological features are helpful to understand how the drug targets work in the PPI network. Particularly, it is an alternative way to predict potential targets or extract nontargets to test a new drug target efficiently and economically. By this way, a drug target's homologue set containing 102 potential target proteins is predicted in the paper.

  5. Drug-targeting methodologies with applications: A review

    PubMed Central

    Kleinstreuer, Clement; Feng, Yu; Childress, Emily

    2014-01-01

    Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

  6. [Monogenic hypercholesterolemias: new genes, new drug targets].

    PubMed

    Mandel'shtam, M Iu; Vasil'ev, V B

    2008-10-01

    This review is focused on recent data on structure and functions of PCSK9 proprotein convertase, a newly identified participant in cholesterol metabolism in mammalian organisms, including humans. Proprotein convertase acts as a molecular chaperone for the low density lipoprotein (LDL) receptor, targeting it to the lysosomal degradation pathway. Various mutations increasing the PCSK9 affinity toward the LDL receptor cause autosomal dominant hypercholesterolemia. In contrast, loss-of-function mutations in PCSK9 gene decrease the blood plasma cholesterol level, thus acting as a protection factor against atherosclerosis and coronary heart disease. It is supposed that pharmacological agents inhibiting the interaction between PCSK9 and LDL receptor may substantially amplify the benefits of drugs--statins and cholesterol absorption blockers--in the treatment of all types of hypercholesterolemia, including its widespread multigenic and multifactorial forms.

  7. Targeting caveolae for vesicular drug transport.

    PubMed

    Gumbleton, Mark; Hollins, Andrew J; Omidi, Yadollah; Campbell, Lee; Taylor, Glyn

    2003-02-21

    Caveolae are morphologically evident as omega-shaped invaginations of the plasma membrane with a diameter of 50-100 nm. They may also exist in a variety of other forms including flattened domains indistinguishable from the plasma membrane itself. At least in some cell types caveolae undertake transport functions including that of the endocytic and transcytotic movement of macromolecules, and indeed microbes and microbial toxins. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit caveolae membrane interactions with the aim to develop of novel cellular or transcellular drug delivery strategies. This overview article will provide: pertinent information on the biology of the caveolae membrane system; review the various caveolae isolation methods; highlight some of the literature evidence showing that caveolae are functional with regard to macromolecule transport; discuss the role that caveolae could fulfill in the pulmonary absorption of therapeutic proteins from alveolar airspace to capillary blood following inhalational drug delivery, and finally review some very recent work showing proof-of-principle that caveolae domains can be targeted in a tissue-specific manner with highly selective ligands.

  8. New Targets for Drug Treatment of Obesity.

    PubMed

    Valsamakis, Georgios; Konstantakou, Panagiota; Mastorakos, George

    2017-01-06

    Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients' needs, resulting in a favorable metabolic profile.

  9. The drug target genes show higher evolutionary conservation than non-target genes.

    PubMed

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

    2016-01-26

    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  10. The Research Progress of Targeted Drug Delivery Systems

    NASA Astrophysics Data System (ADS)

    Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

    2017-06-01

    Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

  11. Network-assisted investigation of antipsychotic drugs and their targets.

    PubMed

    Sun, Jingchun; Xu, Hua; Zhao, Zhongming

    2012-05-01

    Antipsychotic drugs are tranquilizing psychiatric medications primarily used in the treatment of schizophrenia and similar severe mental disorders. So far, most of these drugs have been discovered without knowing much on the molecular mechanisms of their actions. The available large amount of pharmacogenetics, pharmacometabolomics, and pharmacoproteomics data for many drugs makes it possible to systematically explore the molecular mechanisms underlying drug actions. In this study, we applied a unique network-based approach to investigate antipsychotic drugs and their targets. We first retrieved 43 antipsychotic drugs, 42 unique target genes, and 46 adverse drug interactions from the DrugBank database and then generated a drug-gene network and a drug-drug interaction network. Through drug-gene network analysis, we found that seven atypical antipsychotic drugs tended to form two clusters that could be defined by drugs with different target receptor profiles. In the drug-drug interaction network, we found that three drugs (zuclopenthixol, ziprasidone, and thiothixene) tended to have more adverse drug interactions than others, while clozapine had fewer adverse drug interactions. This investigation indicated that these antipsychotics might have different molecular mechanisms underlying the drug actions. This pilot network-assisted investigation of antipsychotics demonstrates that network-based analysis is useful for uncovering the molecular actions of antipsychotics.

  12. DDTRP: Database of Drug Targets for Resistant Pathogens

    PubMed Central

    Sundaramurthi, Jagadish Chandrabose; Ramanandan, Prabhakaran; Brindha, Sridharan; Subhasree, Chelladurai Ramarathnam; Prasad, Abhimanyu; Kumaraswami, Vasanthapuram; Hanna, Luke Elizabeth

    2011-01-01

    Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called ‘Database of Drug Targets for Resistant Pathogens’ (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP. PMID:21938213

  13. Is hippocampal atrophy a future drug target?

    PubMed

    Dhikav, Vikas; Anand, Kuljeet Singh

    2007-01-01

    atrophy would be clinically useful in affecting disease, viz slowing its progression, reducing morbidity, complications or positively affecting the outcome of one or more of its clinically important aspects. If the answer to this is yes, we would have to know at what stage of the disease we use the drugs, dose, duration, follow-up and efficacy. The use of these drugs in the above mentioned conditions can not only test the potential of atrophy as a future drug target, but could also help in learning more about the hippocampus in both health and diseases.

  14. Identifying mechanism-of-action targets for drugs and probes

    PubMed Central

    Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A.; Irwin, John J.; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L.; Shoichet, Brian K.

    2012-01-01

    Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801

  15. The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective.

    PubMed

    Li, Ying Hong; Wang, Pan Pan; Li, Xiao Xu; Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

    2016-01-01

    The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

  16. The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

    PubMed Central

    Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

    2016-01-01

    The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology. PMID:27828998

  17. ING Proteins as Potential Anticancer Drug Targets

    PubMed Central

    Unoki, M.; Kumamoto, K.; Harris, C.C.

    2009-01-01

    Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies. PMID:19442116

  18. Target Essentiality and Centrality Characterize Drug Side Effects

    PubMed Central

    Yu, Haiyuan

    2013-01-01

    To investigate factors contributing to drug side effects, we systematically examine relationships between 4,199 side effects associated with 996 drugs and their 647 human protein targets. We find that it is the number of essential targets, not the number of total targets, that determines the side effects of corresponding drugs. Furthermore, within the context of a three-dimensional interaction network with atomic-resolution interaction interfaces, we find that drugs causing more side effects are also characterized by high degree and betweenness of their targets and highly shared interaction interfaces on these targets. Our findings suggest that both essentiality and centrality of a drug target are key factors contributing to side effects and should be taken into consideration in rational drug design. PMID:23874169

  19. Targeted cancer therapy; nanotechnology approaches for overcoming drug resistance.

    PubMed

    Gao, Yan; Shen, Jacson K; Milane, Lara; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Recent advances in cancer molecular biology have resulted in parallel and unprecedented progress in the development of targeted cancer therapy. Targeted therapy can provide higher efficacy and lower toxicity than conventional chemotherapy for cancer. However, like traditional chemotherapy, molecularly targeted cancer therapy also faces the challenge of drug resistance. Multiple mechanisms are responsible for chemotherapy resistance in tumors, including over-expression of efflux transporters, somatic alterations of drug targets, deregulation of apoptosis, and numerous pharmacokinetic issues. Nanotechnology based approaches are proving to be efficacious in overcoming drug resistance in cancer. Combination of targeted therapies with nanotechnology approaches is a promising strategy to overcome targeted therapy drug resistance in cancer treatment. This review discusses the mechanisms of targeted drug resistance in cancer and discusses nanotechnology approaches to circumvent this resistance.

  20. TRP Channels as Potential Drug Targets.

    PubMed

    Moran, Magdalene M

    2017-09-25

    The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. The import of these channels is underscored by the number of genetic diseases caused when they are mutated: Skeletal, skin, sensory, ocular, cardiac, and neuronal disturbances all arise from aberrant TRP function. Not surprisingly, there has been significant pharmaceutical interest in targeting these fascinating channels. Compounds that modulate TRP vanilloid 1 (TRPV1), TRPV3, TRPV4, TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) have all entered clinical trials. The goal of this review is to familiarize the readers with the rationale behind the pursuit of these channels in drug discovery and the status of those efforts. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  1. Giant Fullerenes for Target Specific Drug Delivery

    NASA Astrophysics Data System (ADS)

    Courtney, Robert; Kiefer, Boris

    2013-03-01

    Carbon nano-structures, such as giant fullerenes, have a great potential for biological and medical applications. Most of the previous research is dedicated to investigate the use of fullerenes as vehicles for carrying medication which is chemisorbed on the outside surface of the fullerenes. In contrast, using fullerenes as an enclosure was largely abandoned due to the high strength of the carbon-carbon bonds which has been perceived to prevent the rupturing of the fullerene to release their cargo. We performed atomistic computations based on classical force fields that will address this perception. Specifically we explore the physics and chemistry of OH functionalized carbon based giant fullerenes with diameters from 0.72 nm (60 atoms) to 5.7 nm (3840 atoms). The preliminary results show that OH functionalization on these fullerenes is not only viable but also provides a pH sensitive release mechanism. Furthermore our current results show that carbon-carbon bonds can be broken in low energy biological environments in the presence of a flow induced strain field. These insights may have implications for target specific drug delivery in general and cancer treatment in particular. We gratefully acknowledge support from BP-ENDURE (NIH R25GM097633).

  2. Deep-Learning-Based Drug-Target Interaction Prediction.

    PubMed

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-04-07

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  3. Weighted feature value based Drug Target Protein prediction.

    PubMed

    Hyun, Bo-ra; Jung, Hwiesung; Jang, Woo-Hyuk; Jung, Suk Hoon; Han, Dong-Soo

    2008-01-01

    Drug discovery is a long process in which only a few successful new therapeutic discoveries are made and identification of drug target candidate proteins requires considerable time and efforts. However, the accumulation of information on drugs has made it possible to devise new computational methods for classifying drug target candidates. In this paper, we devise a Drug Target Protein (DT-P) classification method by the summation of weighted features which is extracted from known DT-P. The method is validated using Bayesian decision theory and SVM, and it was revealed to achieve high specificity of 89.5% with 88% accuracy.

  4. Drug target prioritization by perturbed gene expression and network information

    PubMed Central

    Isik, Zerrin; Baldow, Christoph; Cannistraci, Carlo Vittorio; Schroeder, Michael

    2015-01-01

    Drugs bind to their target proteins, which interact with downstream effectors and ultimately perturb the transcriptome of a cancer cell. These perturbations reveal information about their source, i.e., drugs’ targets. Here, we investigate whether these perturbations and protein interaction networks can uncover drug targets and key pathways. We performed the first systematic analysis of over 500 drugs from the Connectivity Map. First, we show that the gene expression of drug targets is usually not significantly affected by the drug perturbation. Hence, expression changes after drug treatment on their own are not sufficient to identify drug targets. However, ranking of candidate drug targets by network topological measures prioritizes the targets. We introduce a novel measure, local radiality, which combines perturbed genes and functional interaction network information. The new measure outperforms other methods in target prioritization and proposes cancer-specific pathways from drugs to affected genes for the first time. Local radiality identifies more diverse targets with fewer neighbors and possibly less side effects. PMID:26615774

  5. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    PubMed Central

    Mukherjee, Avinaba; Sadhukhan, Gobinda Chandra

    2016-01-01

    Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug resistance. PMID

  6. Sequencing: Targeting Insurgents and Drugs in Colombia

    DTIC Science & Technology

    2007-03-01

    examines the overall effectiveness of two distinctly different strategies for dealing with the dual threat of drugs and terrorism in Colombia: President...Drug Trade, Coca, Counter-narcotics, FARC, FARC-EP, Revolutionary Armed Forces of Colombia, Government of Colombia, Insurgency, Terrorism , Plan...threat of drugs and terrorism in Colombia: President Pastrana’s “drugs first” strategy and President Uribe’s unified campaign against both guerrillas

  7. Target based drug design - a reality in virtual sphere.

    PubMed

    Verma, Saroj; Prabhakar, Yenamandra S

    2015-01-01

    The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

  8. Assessing drug target association using semantic linked data.

    PubMed

    Chen, Bin; Ding, Ying; Wild, David J

    2012-01-01

    The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a [Formula: see text] score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.

  9. A weighted and integrated drug-target interactome: drug repurposing for schizophrenia as a use case

    PubMed Central

    2015-01-01

    Background Computational pharmacology can uniquely address some issues in the process of drug development by providing a macroscopic view and a deeper understanding of drug action. Specifically, network-assisted approach is promising for the inference of drug repurposing. However, the drug-target associations coming from different sources and various assays have much noise, leading to an inflation of the inference errors. To reduce the inference errors, it is necessary and critical to create a comprehensive and weighted data set of drug-target associations. Results In this study, we created a weighted and integrated drug-target interactome (WinDTome) to provide a comprehensive resource of drug-target associations for computational pharmacology. We first collected drug-target interactions from six commonly used drug-target centered data sources including DrugBank, KEGG, TTD, MATADOR, PDSP Ki Database, and BindingDB. Then, we employed the record linkage method to normalize drugs and targets to the unique identifiers by utilizing the public data sources including PubChem, Entrez Gene, and UniProt. To assess the reliability of the drug-target associations, we assigned two scores (Score_S and Score_R) to each drug-target association based on their data sources and publication references. Consequently, the WinDTome contains 546,196 drug-target associations among 303,018 compounds and 4,113 genes. To assess the application of the WinDTome, we designed a network-based approach for drug repurposing using mental disorder schizophrenia (SCZ) as a case. Starting from 41 known SCZ drugs and their targets, we inferred a total of 264 potential SCZ drugs through the associations of drug-target with Score_S higher than two in WinDTome and human protein-protein interactions. Among the 264 SCZ-related drugs, 39 drugs have been investigated in clinical trials for SCZ treatment and 74 drugs for the treatment of other mental disorders, respectively. Compared with the results using other

  10. An eigenvalue transformation technique for predicting drug-target interaction.

    PubMed

    Kuang, Qifan; Xu, Xin; Li, Rong; Dong, Yongcheng; Li, Yan; Huang, Ziyan; Li, Yizhou; Li, Menglong

    2015-09-09

    The prediction of drug-target interactions is a key step in the drug discovery process, which serves to identify new drugs or novel targets for existing drugs. However, experimental methods for predicting drug-target interactions are expensive and time-consuming. Therefore, the in silico prediction of drug-target interactions has recently attracted increasing attention. In this study, we propose an eigenvalue transformation technique and apply this technique to two representative algorithms, the Regularized Least Squares classifier (RLS) and the semi-supervised link prediction classifier (SLP), that have been used to predict drug-target interaction. The results of computational experiments with these techniques show that algorithms including eigenvalue transformation achieved better performance on drug-target interaction prediction than did the original algorithms. These findings show that eigenvalue transformation is an efficient technique for improving the performance of methods for predicting drug-target interactions. We further show that, in theory, eigenvalue transformation can be viewed as a feature transformation on the kernel matrix. Accordingly, although we only apply this technique to two algorithms in the current study, eigenvalue transformation also has the potential to be applied to other algorithms based on kernels.

  11. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    PubMed Central

    Park, Yoon-Dong; Sun, Wei; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Wang, Amy; Xu, Xin; Meng, Zhaojin; Zhou, Ming; Tawa, Gregory J.; Dehdashti, Jean; Zheng, Wei; Henderson, Christina M.; Zelazny, Adrian M.

    2016-01-01

    ABSTRACT Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. PMID:27486194

  12. Toward more realistic drug-target interaction predictions.

    PubMed

    Pahikkala, Tapio; Airola, Antti; Pietilä, Sami; Shakyawar, Sushil; Szwajda, Agnieszka; Tang, Jing; Aittokallio, Tero

    2015-03-01

    A number of supervised machine learning models have recently been introduced for the prediction of drug-target interactions based on chemical structure and genomic sequence information. Although these models could offer improved means for many network pharmacology applications, such as repositioning of drugs for new therapeutic uses, the prediction models are often being constructed and evaluated under overly simplified settings that do not reflect the real-life problem in practical applications. Using quantitative drug-target bioactivity assays for kinase inhibitors, as well as a popular benchmarking data set of binary drug-target interactions for enzyme, ion channel, nuclear receptor and G protein-coupled receptor targets, we illustrate here the effects of four factors that may lead to dramatic differences in the prediction results: (i) problem formulation (standard binary classification or more realistic regression formulation), (ii) evaluation data set (drug and target families in the application use case), (iii) evaluation procedure (simple or nested cross-validation) and (iv) experimental setting (whether training and test sets share common drugs and targets, only drugs or targets or neither). Each of these factors should be taken into consideration to avoid reporting overoptimistic drug-target interaction prediction results. We also suggest guidelines on how to make the supervised drug-target interaction prediction studies more realistic in terms of such model formulations and evaluation setups that better address the inherent complexity of the prediction task in the practical applications, as well as novel benchmarking data sets that capture the continuous nature of the drug-target interactions for kinase inhibitors. © The Author 2014. Published by Oxford University Press.

  13. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter.

    PubMed

    Gilbert, Ian H

    2014-01-01

    Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.

  14. Targeted drug-carrying bacteriophages as antibacterial nanomedicines.

    PubMed

    Yacoby, Iftach; Bar, Hagit; Benhar, Itai

    2007-06-01

    While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of approximately 20,000 compared to the free drug.

  15. Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

    PubMed Central

    Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

    2015-01-01

    Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates. PMID:25960144

  16. Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

    NASA Astrophysics Data System (ADS)

    Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

    2015-05-01

    Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.

  17. Magnetic polymer nanospheres for anticancer drug targeting

    NASA Astrophysics Data System (ADS)

    Juríková, A.; Csach, K.; Koneracká, M.; Závišová, V.; Múčková, M.; Tomašovičová, N.; Lancz, G.; Kopčanský, P.; Timko, M.; Miškuf, J.

    2010-01-01

    Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

  18. Gaussian interaction profile kernels for predicting drug-target interaction.

    PubMed

    van Laarhoven, Twan; Nabuurs, Sander B; Marchiori, Elena

    2011-11-01

    The in silico prediction of potential interactions between drugs and target proteins is of core importance for the identification of new drugs or novel targets for existing drugs. However, only a tiny portion of all drug-target pairs in current datasets are experimentally validated interactions. This motivates the need for developing computational methods that predict true interaction pairs with high accuracy. We show that a simple machine learning method that uses the drug-target network as the only source of information is capable of predicting true interaction pairs with high accuracy. Specifically, we introduce interaction profiles of drugs (and of targets) in a network, which are binary vectors specifying the presence or absence of interaction with every target (drug) in that network. We define a kernel on these profiles, called the Gaussian Interaction Profile (GIP) kernel, and use a simple classifier, (kernel) Regularized Least Squares (RLS), for prediction drug-target interactions. We test comparatively the effectiveness of RLS with the GIP kernel on four drug-target interaction networks used in previous studies. The proposed algorithm achieves area under the precision-recall curve (AUPR) up to 92.7, significantly improving over results of state-of-the-art methods. Moreover, we show that using also kernels based on chemical and genomic information further increases accuracy, with a neat improvement on small datasets. These results substantiate the relevance of the network topology (in the form of interaction profiles) as source of information for predicting drug-target interactions. Software and Supplementary Material are available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2011/. tvanlaarhoven@cs.ru.nl; elenam@cs.ru.nl. Supplementary data are available at Bioinformatics online.

  19. Identification of human drug targets using machine-learning algorithms.

    PubMed

    Kumari, Priyanka; Nath, Abhigyan; Chaube, Radha

    2015-01-01

    Identification of potential drug targets is a crucial task in the drug-discovery pipeline. Successful identification of candidate drug targets in entire genomes is very useful, and computational prediction methods can speed up this process. In the current work we have developed a sequence-based prediction method for the successful identification and discrimination of human drug target proteins, from human non-drug target proteins. The training features include sequence-based features, such as amino acid composition, amino acid property group composition, and dipeptide composition for generating predictive models. The classification of human drug target proteins presents a classic example of class imbalance. We have addressed this issue by using SMOTE (Synthetic Minority Over-sampling Technique) as a preprocessing step, for balancing the training data with a ratio of 1:1 between drug targets (minority samples) and non-drug targets (majority samples). Using ensemble classification learning method-Rotation Forest and ReliefF feature-selection technique for selecting the optimal subset of salient features, the best model with selected features can achieve 87.1% sensitivity, 83.6% specificity, and 85.3% accuracy, with 0.71 Matthews correlation coefficient (mcc) on a tenfold stratified cross-validation test. The subset of identified optimal features may help in assessing the compositional patterns in human drug targets. For further validation, using a rigorous leave-one-out cross-validation test, the model achieved 88.1% sensitivity, 83.0% specificity, 85.5% accuracy, and 0.712 mcc. The proposed method was tested on a second dataset, for which the current pipeline gave promising results. We suggest that the present approach can be applied successfully as a complementary tool to existing methods for novel drug target prediction. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Targeted drug induces responses in aggressive lymphomas

    Cancer.gov

    Preliminary results from clinical trials in a subtype of lymphoma show that for a number of patients whose disease was not cured by other treatments, the drug ibrutinib can provide significant anti-cancer responses with modest side effects.

  1. Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space.

    PubMed

    Peón, Antonio; Naulaerts, Stefan; Ballester, Pedro J

    2017-06-19

    Many computational methods to predict the macromolecular targets of small organic molecules have been presented to date. Despite progress, target prediction methods still have important limitations. For example, the most accurate methods implicitly restrict their predictions to a relatively small number of targets, are not systematically validated on drugs (whose targets are harder to predict than those of non-drug molecules) and often lack a reliability score associated with each predicted target. Here we present a systematic validation of ligand-centric target prediction methods on a set of clinical drugs. These methods exploit a knowledge-base covering 887,435 known ligand-target associations between 504,755 molecules and 4,167 targets. Based on this dataset, we provide a new estimate of the polypharmacology of drugs, which on average have 11.5 targets below IC50 10 µM. The average performance achieved across clinical drugs is remarkable (0.348 precision and 0.423 recall, with large drug-dependent variability), especially given the unusually large coverage of the target space. Furthermore, we show how a sparse ligand-target bioactivity matrix to retrospectively validate target prediction methods could underestimate prospective performance. Lastly, we present and validate a first-in-kind score capable of accurately predicting the reliability of target predictions.

  2. Drug efflux pump deficiency and drug target resistance masking in growing bacteria

    PubMed Central

    Fange, David; Nilsson, Karin; Tenson, Tanel; Ehrenberg, Måns

    2009-01-01

    Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to “mask” the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens. PMID:19416855

  3. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation.

    PubMed

    de Witte, W E A; Vauquelin, G; van der Graaf, P H; de Lange, E C M

    2017-05-12

    The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a locally higher drug concentration that arises around the target, which leads to prolonged target exposure to the drug. This phenomenon has been approximated by the steady-state approximation, assuming a steady-state concentration around the target. Recently, a rate-limiting step approximation of drug distribution and drug-target binding has been published. However, a comparison between both approaches has not been made so far. In this study, the rate-limiting step approximation has been rewritten into the same mathematical format as the steady-state approximation in order to compare the performance of both approaches for the investigation of the influence of drug-target binding kinetics on target occupancy. While both approximations clearly indicated the importance of kon and high target concentrations, it was shown that the rate-limiting step approximation is more accurate than the steady-state approximation, especially when dissociation is fast compared to association and distribution out of the binding compartment. It is therefore concluded that the new rate-limiting step approximation is to be preferred for assessing the influence of binding kinetics on local target site concentrations and target occupancy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for Plasmodium falciparum.

    PubMed

    Qidwai, Tabish; Jamal, Farrukh; Khan, Mohd Y; Sharma, Bechan

    2014-01-01

    Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

  5. Aging Biology and Novel Targets for Drug Discovery

    PubMed Central

    McLachlan, Andrew J.; Quinn, Ronald J.; Simpson, Stephen J.; de Cabo, Rafael

    2012-01-01

    Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. PMID:21693687

  6. Plasmodium Drug Targets Outside the Genetic Control of the Parasite

    PubMed Central

    Sullivan, David J.

    2014-01-01

    Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition. PMID:22973888

  7. Biodegradable polymers for targeted delivery of anti-cancer drugs.

    PubMed

    Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

    2016-06-01

    Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

  8. Mouse model phenotypes provide information about human drug targets

    PubMed Central

    Hoehndorf, Robert; Hiebert, Tanya; Hardy, Nigel W.; Schofield, Paul N.; Gkoutos, Georgios V.; Dumontier, Michel

    2014-01-01

    Motivation: Methods for computational drug target identification use information from diverse information sources to predict or prioritize drug targets for known drugs. One set of resources that has been relatively neglected for drug repurposing is animal model phenotype. Results: We investigate the use of mouse model phenotypes for drug target identification. To achieve this goal, we first integrate mouse model phenotypes and drug effects, and then systematically compare the phenotypic similarity between mouse models and drug effect profiles. We find a high similarity between phenotypes resulting from loss-of-function mutations and drug effects resulting from the inhibition of a protein through a drug action, and demonstrate how this approach can be used to suggest candidate drug targets. Availability and implementation: Analysis code and supplementary data files are available on the project Web site at https://drugeffects.googlecode.com. Contact: leechuck@leechuck.de or roh25@aber.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:24158600

  9. Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to Overcome Drug Resistance.

    PubMed

    Gong, Meng-Qing; Wu, Cong; He, Xiao-Yan; Zong, Jing-Yi; Wu, Jin-Long; Zhuo, Ren-Xi; Cheng, Si-Xue

    2017-01-01

    To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed. To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells. Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR). The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug

  10. Drug-Loaded Polymeric Nanoparticles for Cancer Stem Cell Targeting

    PubMed Central

    Li, Binbin; Li, Qinghua; Mo, Jingxin; Dai, Honglian

    2017-01-01

    Cancer stem cells (CSCs) have been reported to play critical roles in tumor initiation, propagation, and regeneration of cancer. Nano-size vehicles are employed to deliver drugs to target the CSCs for cancer therapy. Polymeric nanoparticles have been considered as the most efficient vehicles for drug delivery due to their excellent pharmacokinetic properties. The CSCs specific antibodies or ligands can be conjugated onto the surface or interior of nanoparticles to successfully target and finally eliminate CSCs. In this review, we focus on the approaches of polymeric nanoparticles design for loading drug, and their potential application for CSCs targeting in cancer therapy. PMID:28261093

  11. Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery

    PubMed Central

    Scott, Latanya. M.; Lawrence, Harshani. R.; Sebti, Saïd. M.; Lawrence, Nicholas. J.; Wu, Jie.

    2010-01-01

    Protein tyrosine phosphatases (PTPs) are a diverse family of enzymes encoded by 107 genes in the human genome. Together with protein tyrosine kinases (PTKs), PTPs regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. While PTK inhibitors are now used routinely for cancer treatment, the PTP inhibitor development field is still in the discovery phase. In this article, the suitability of targeting PTPs for novel anticancer drug discovery is discussed. Examples are presented for PTPs that have been targeted for anticancer drug discovery as well as potential new PTP targets for novel anticancer drug discovery. PMID:20337577

  12. Hemozoin Formation as a Target for Antimalarial Drug Design

    DTIC Science & Technology

    2005-02-01

    AD Award Number: DAMD17-03-1-0030 TITLE: Hemozoin Formation as a Target for Antimalarial Drug Design PRINCIPAL INVESTIGATOR: Michael K. Riscoe, Ph.D...Formation as a Target for Antimalarial Drug Design DAMD17-03-1-0030 6. A UTHOR(S) Michael K. Riscoe, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S) AND ADDRESS...Report: by Principal Investigator - Michael K. Riscoe, Ph.D. DAMD1 7-03-1-0030: "Hemozoin Formation as a Target for Antimalarial Drug Design " INTRODUCTION

  13. Cartilage-targeting drug delivery: can electrostatic interactions help?

    PubMed

    Bajpayee, Ambika G; Grodzinsky, Alan J

    2017-03-01

    Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge-charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.

  14. Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases.

    PubMed

    Koch, Gilbert; Jusko, William J; Schropp, Johannes

    2017-02-01

    We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation.

  15. Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems.

    PubMed

    Maity, Amit Ranjan; Stepensky, David

    2016-01-04

    Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting.

  16. DrugComboRanker: drug combination discovery based on target network analysis

    PubMed Central

    Huang, Lei; Li, Fuhai; Sheng, Jianting; Xia, Xiaofeng; Ma, Jinwen; Zhan, Ming; Wong, Stephen T.C.

    2014-01-01

    Motivation: Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients’ outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities. Results: In this study, we propose a novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients’ genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the

  17. Chemical proteomics: terra incognita for novel drug target profiling

    PubMed Central

    Huang, Fuqiang; Zhang, Boya; Zhou, Shengtao; Zhao, Xia; Bian, Ce; Wei, Yuquan

    2012-01-01

    The growing demand for new therapeutic strategies in the medical and pharmaceutic fields has resulted in a pressing need for novel druggable targets. Paradoxically, however, the targets of certain drugs that are already widely used in clinical practice have largely not been annotated. Because the pharmacologic effects of a drug can only be appreciated when its interactions with cellular components are clearly delineated, an integrated deconvolution of drug-target interactions for each drug is necessary. The emerging field of chemical proteomics represents a powerful mass spectrometry (MS)-based affinity chromatography approach for identifying proteome-wide small molecule-protein interactions and mapping these interactions to signaling and metabolic pathways. This technique could comprehensively characterize drug targets, profile the toxicity of known drugs, and identify possible off-target activities. With the use of this technique, candidate drug molecules could be optimized, and predictable side effects might consequently be avoided. Herein, we provide a holistic overview of the major chemical proteomic approaches and highlight recent advances in this area as well as its potential applications in drug discovery. PMID:22640626

  18. Targeted Cellular Drug Delivery using Tailored Dendritic Nanostructures

    NASA Astrophysics Data System (ADS)

    Kannan, Rangaramanujam; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

    2002-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorble, ‘peripheral’ functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug and gene delivery. The large number of end groups can also be tailored to create special affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, in-vitro drug loading, in-vitro drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Polyamidoamine and Polyol dendrimers, with different generations and end-groups are studied, with drugs such as Ibuprofen and Methotrexate. Our results indicate that a large number of drug molecules can be encapsulated/attached to the dendrimers, depending on the end groups. The drug-encapsulated dendrimer is able to enter the cells rapidly and deliver the drug. Targeting strategies being explored

  19. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    PubMed

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  20. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    NASA Astrophysics Data System (ADS)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  1. Humanized docking system for assembly of targeting drug delivery complexes.

    PubMed

    Backer, Marina V; Gaynutdinov, Timur I; Gorshkova, Inna I; Crouch, Robert J; Hu, Tao; Aloise, Renee; Arab, Mohamed; Przekop, Kristen; Backer, Joseph M

    2003-05-20

    Targeted drug delivery requires 'loading' drugs onto targeting proteins. Traditional technologies for loading drugs rely on chemical conjugation of drugs or drug carriers to targeting proteins. An alternative approach might rely on assembly of targeting complexes using a docking system that includes two components: a 'docking' tag fused to a targeting protein, and a 'payload' module containing an adapter protein for non-covalent binding to the docking tag. We describe here a fully humanized adapter/docking tag system based on non-covalent interaction between two fragments of human pancreatic RNase I. A 15 amino acid long N-terminal fragment of RNase I designed to serve as a docking tag, was fused to the N-terminus of human vascular endothelial growth factor that served as a targeting protein. An 18-125 and an 18-127 amino acid long fragments of RNase I were engineered, expressed and refolded into active conformations to serve as adapter proteins. Interactions between the targeting and adapter proteins were characterized using enzymatic analysis and surface plasmon resonance. Targeting DNA delivery complexes were assembled, characterized by dynamic light scattering, and found to be very effective in receptor-mediated DNA delivery.

  2. Topoisomerase as target for antibacterial and anticancer drug discovery.

    PubMed

    Kathiravan, Muthu K; Khilare, Madhavi M; Nikoomanesh, Kiana; Chothe, Aparna S; Jain, Kishor S

    2013-06-01

    DNA topoisomerases comprise a major aspect of basic cellular biology and are molecular targets for a variety of drugs like antibiotics, antibacterials and anticancer drugs. They act by inhibiting the topoisomerase molecule from relegating DNA strands after cleavage and convert the topoisomerases molecule into a DNA damaging agent. Though drugs of various categories acting through different mechanisms are available for the treatment, there are still problems associated with the currently available drugs. Therefore, Structural biologists, Structural chemists and Medicinal chemists all around the world have been identifying, designing, synthesizing and evaluating a variety of novel bioactive molecules targeting topoisomerase. This review summarizes types of topoisomerase and drug treating each class along with their structural requirement and activity. The emphasis has been laid in particular on the new potential heterocyles and the possible treatments as well as the current ongoing research status in the field of topoisomerase as dual targeting.

  3. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma

    PubMed Central

    Tavanti, E; Sero, V; Vella, S; Fanelli, M; Michelacci, F; Landuzzi, L; Magagnoli, G; Versteeg, R; Picci, P; Hattinger, C M; Serra, M

    2013-01-01

    Background: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. Methods: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines. Results: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments. Conclusion: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents. PMID:24129234

  4. Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

    PubMed Central

    Ren, Muqing; Duval, Kayla; Guo, Xing; Chen, Zi

    2016-01-01

    Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this article, we provide an overview of three different targeted drug delivery methods (passive targeting, active targeting and physical targeting), compare methods of action, advantages, limitations, and the current stage of research. For the most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computational simulations and models on nanoparticle-based drug delivery. PMID:27398083

  5. Leveraging big data to transform target selection and drug discovery

    PubMed Central

    Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  6. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    DTIC Science & Technology

    2013-08-01

    vesicular stomatitis virus (VSV) can exert a dual antitumor effect by triggering direct tumor lysis and eliciting tumor specific immunity. VSV can also...tumors, and the levels of infiltrating leukocytes were similar across the VSV-treated tumors. Altogether the data indicate that VSV-based therapy is...effective against a cisplatin-resistant lung tumor model. 15. SUBJECT TERMS Drug resistance, oncolytic virotherapy, vesicular stomatitis virus, lung

  7. Chemokine receptors: attractive targets for drug discovery.

    PubMed

    Godessart, Nuria

    2005-06-01

    Studies of two antibodies, efalizumab and natalizumab, have recently demonstrated that the blockade of leukocyte migration is of therapeutic benefit for the treatment of diseases such as psoriasis and multiple sclerosis. The role of chemokines in the control of cell traffic led to their receptors being considered one of the most promising family of targets aimed at disrupting cell recruitment in chronic inflammatory processes. Choosing the appropriate chemokine receptor for each disease was not easy, and the interpretation of target validation studies proved to be extremely difficult. Despite an intense effort in the search for chemokine receptor antagonists in the last decade, no compounds in advanced clinical trials exist as such. The inherent complexity of the family, the differences between the chemokine system in mice and men, and the species selectivity of small-molecule compounds could account for this fact. Pharmaceutical companies still believe in chemokine receptors as therapeutic targets, as demonstrated by the number of compounds reported to be in development. In the next years, the developmental progression of these compounds will reveal which target within the chemokine family is of real therapeutic value.

  8. Aiming drug discovery at lysophosphatidic acid targets

    PubMed Central

    Tigyi, Gabor

    2010-01-01

    Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons. PMID:20735414

  9. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    DTIC Science & Technology

    2016-06-01

    AWARD NUMBER: W81XWH-13-1-0429 TITLE: Using "Click Chemistry " to Identify Potential Drug Targets in Plasmodium PRINCIPAL INVESTIGATOR...29Mar2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0429 Using click chemistry to identify potential drug targets in Plasmodium 5b...Al-Tsp derivatives begins. Two classes of Tsp derivatives (Al-Tsp) are appropriate for click chemistry (Fig. 1). Class I derivatives carry a

  10. Predicting drug-target interactions using restricted Boltzmann machines

    PubMed Central

    Wang, Yuhao; Zeng, Jianyang

    2013-01-01

    Motivation: In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. Results: We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Availability: Software and datasets are available

  11. Ex vivo investigation of magnetically targeted drug delivery system

    NASA Astrophysics Data System (ADS)

    Yoshida, Y.; Fukui, S.; Fujimoto, S.; Mishima, F.; Takeda, S.; Izumi, Y.; Ohtani, S.; Fujitani, Y.; Nishijima, S.

    2007-03-01

    In conventional systemic drug delivery the drug is administered by intravenous injection; it then travels to the heart from where it is pumped to all regions of the body. When the drug is aimed at a small target region, this method is extremely inefficient and leads to require much larger doses than those being necessary. In order to overcome this problem a number of targeted drug delivery methods are developed. One of these, magnetically targeted drug delivery system (MT-DDS) will be a promising way, which involves binding a drug to small biocompatible magnetic particles, injecting these into the blood stream and using a high gradient magnetic field to pull them out of suspension in the target region. In the present paper, we describe an ex vivo experimental work. It is also reported that navigation and accumulation test of the magnetic particles in the Y-shaped glass tube was performed in order to examine the threshold of the magnetic force for accumulation. It is found that accumulation of the magnetic particles was succeeded in the blood vessel when a permanent magnet was placed at the vicinity of the blood vessel. This result indicates the feasibility of the magnetically drug targeting in the blood vessel.

  12. Is the Mitochondrion a Good Malaria Drug Target?

    PubMed

    Goodman, Christopher D; Buchanan, Hayley D; McFadden, Geoffrey I

    2017-03-01

    Rapid emergence of resistance to atovaquone, which targets electron transport in the malaria parasite mitochondrion, relegated its use to prophylaxis and even cast a shadow over the development of drugs targeting other parasite mitochondrial pathways. Here we argue for a renewed focus on the mitochondrion as a drug target, focusing particularly on the issues of resistance. We posit a hypothesis for why atovaquone resistance emerges so quickly, and we explain how facile acquisition of resistance is apparently offset by an inability of parasites to spread this resistance. We also explore the utility and resistance issues for emerging new drugs targeting parasite mitochondria, concluding that the mitochondrion is indeed an excellent target. Copyright © 2016. Published by Elsevier Ltd.

  13. CNIO cancer conference: targeted search for anticancer drugs.

    PubMed

    Fischer, Peter M

    2003-06-01

    The topics discussed at the conference covered many aspects of cancer research, from the genetic search for new targets, target validation and drug discovery, all the way to preclinical and clinical development of oncology drugs. Here the presentations on new metabolic, angiogenic, cell cycle and other molecular targets, as well as recent developments with experimental drugs with action on some of these targets, are summarised. Particular emphasis is placed on the emerging realisation that changes in the metabolic phenotype lie at the heart of cellular transformation. New insights into the biological links between cancer cell metabolism and the balance between survival and death signalling are likely to lead to the identification of a new category of anticancer targets.

  14. The path to oncology drug target validation: an industry perspective.

    PubMed

    Cortés-Cros, Marta; Schmelzle, Tobias; Stucke, Volker M; Hofmann, Francesco

    2013-01-01

    The advent of a variety of genomic, proteomic and other system-based scientific approaches has raised the expectations of identifying novel targets for oncology drug discovery. However, the complexity of human genome cancer alterations requires a careful analysis of the function of candidate targets identified by these efforts. The postulation and testing of a hypothesis that modulation of a protein or pathway will result in a therapeutic effect in a preclinical setting is crucial for target validation activities. In this chapter, we provide an overview on target identification and validation approaches to interrogate the functional and therapeutic relevance of a candidate cancer drug target as an essential step towards justifying the subsequent investment in drug discovery efforts.

  15. Drug target identification in intracellular and extracellular protozoan parasites.

    PubMed

    Müller, Joachim; Hemphill, Andrew

    2011-01-01

    The increasing demand for novel anti-parasitic drugs due to resistance formation to well-established chemotherapeutically important compounds has increased the demands for a better understanding of the mechanism(s) of action of existing drugs and of drugs in development. While different approaches have been developed to identify the targets and thus mode of action of anti-parasitic compounds, it has become clear that many drugs act not only on one, but possibly several parasite molecules or even pathways. Ideally, these targets are not present in any cells of the host. In the case of apicomplexan parasites, the unique apicoplast, provides a suitable target for compounds binding to DNA or ribosomal RNA of prokaryotic origin. In the case of intracellular pathogens, a given drug might not only affect the pathogen by directly acting on parasite-associated targets, but also indirectly, by altering the host cell physiology. This in turn could affect the parasite development and lead to parasite death. In this review, we provide an overview of strategies for target identification, and present examples of selected drug targets, ranging from proteins to nucleic acids to intermediary metabolism.

  16. Computational Drug Target Screening through Protein Interaction Profiles

    PubMed Central

    Vilar, Santiago; Quezada, Elías; Uriarte, Eugenio; Costanzi, Stefano; Borges, Fernanda; Viña, Dolores; Hripcsak, George

    2016-01-01

    The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50 values of 25 and 65 μM respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3′-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50 in hCOX-1 of 24 and 25 μM respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin-3′-monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25 μM respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safety. PMID:27845365

  17. Detecting drug targets with minimum side effects in metabolic networks.

    PubMed

    Li, Z; Wang, R-S; Zhang, X-S; Chen, L

    2009-11-01

    High-throughput techniques produce massive data on a genome-wide scale which facilitate pharmaceutical research. Drug target discovery is a crucial step in the drug discovery process and also plays a vital role in therapeutics. In this study, the problem of detecting drug targets was addressed, which finds a set of enzymes whose inhibition stops the production of a given set of target compounds and meanwhile minimally eliminates non-target compounds in the context of metabolic networks. The model aims to make the side effects of drugs as small as possible and thus has practical significance of potential pharmaceutical applications. Specifically, by exploiting special features of metabolic systems, a novel approach was proposed to exactly formulate this drug target detection problem as an integer linear programming model, which ensures that optimal solutions can be found efficiently without any heuristic manipulations. To verify the effectiveness of our approach, computational experiments on both Escherichia coli and Homo sapiens metabolic pathways were conducted. The results show that our approach can identify the optimal drug targets in an exact and efficient manner. In particular, it can be applied to large-scale networks including the whole metabolic networks from most organisms.

  18. NIH tools facilitate matching cancer drugs with gene targets

    Cancer.gov

    A new study details how a suite of web-based tools provides the research community with greatly improved capacity to compare data derived from large collections of genomic information against thousands of drugs. By comparing drugs and genetic targets, re

  19. Dendrimeric micelles for controlled drug release and targeted delivery

    PubMed Central

    Ambade, Ashootosh V.; Savariar, Elamprakash N.; Thayumanavan, S.

    2008-01-01

    This review highlights the developments in dendrimer-based micelles for drug delivery. Dendrimers, the perfectly branched monodisperse macromolecules, have certain structural advantages that make them attractive candidates as drug carriers for controlled release or targeted delivery. As polymeric micelle-based approaches precede the work in dendrimers, these are also discussed briefly. The review concludes with a perspective on possible applications of biaryl-based dendrimeric micelles that exhibit environment-dependent conformations, in drug delivery. PMID:16053329

  20. Dominant drug targets suppress the emergence of antiviral resistance

    PubMed Central

    Tanner, Elizabeth J; Liu, Hong-mei; Oberste, M Steven; Pallansch, Mark; Collett, Marc S; Kirkegaard, Karla

    2014-01-01

    The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a ‘dominant drug target’ suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu. DOI: http://dx.doi.org/10.7554/eLife.03830.001 PMID:25365453

  1. Epigenetic drug discovery: targeting DNA methyltransferases.

    PubMed

    Foulks, Jason M; Parnell, K Mark; Nix, Rebecca N; Chau, Suzanna; Swierczek, Krzysztof; Saunders, Michael; Wright, Kevin; Hendrickson, Thomas F; Ho, Koc-Kan; McCullar, Michael V; Kanner, Steven B

    2012-01-01

    Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets. This review focuses on the rationale of targeting DNMTs in cancer, the historical approach to DNMT inhibition, and current marketed hypomethylating therapeutics azacytidine and decitabine. In addition, we address novel DNMT inhibitory agents emerging in development, including CP-4200 and SGI-110, analogs of azacytidine and decitabine, respectively; the oligonucleotides MG98 and miR29a; and a number of reversible inhibitors, some of which appear to be selective against particular DNMT isoforms. Finally, we discuss future opportunities and challenges for next-generation therapeutics.

  2. Nonantimicrobial drug targets for Clostridium difficile infections.

    PubMed

    Darkoh, Charles; Deaton, Magdalena; DuPont, Herbert L

    2017-09-01

    Clostridium difficile infection (CDI) is a major public health problem worldwide. Treatment has become complicated due to the emergence of strains with increased toxigenicity and sporulation rate, together with rampant antibiotics use that disrupts colonization resistance of the colonic microbiota. As a result, there is a critical need for nonantibiotic treatments. Therapies based on inhibiting the toxins, bacterial structures responsible for colonization, virulence and restoration of the gut microbiota are the most important nonantibiotic targets to combat CDI. This report outlines these targets and how they could become the focus of future therapeutic agents. Inhibiting colonization and virulence factors during CDI will disrupt pathogen persistence and decrease exposure to the inflammatory toxins, allowing the immune system to clear the infection.

  3. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    DTIC Science & Technology

    2014-10-01

    both oncolysis and induction of specific tumor-targeted immune responses in the host (4). Because viral oncolysis has a potential to induce tumor...intervention using viral delivery of cDNA from the same cell population. We hypothesize that the delivery of a tumor antigen library 5 derived from a...infection (MOIs) of VSV expressing green fluorescent protein (GFP) and analyzed by flow cytometry and plaque assay for VSV replication and induction

  4. Synthetic LDL as targeted drug delivery vehicle

    DOEpatents

    Forte, Trudy M [Berkeley, CA; Nikanjam, Mina [Richmond, CA

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  5. Prediction of Drug-Target Interactions for Drug Repositioning Only Based on Genomic Expression Similarity

    PubMed Central

    Wang, Kejian; Sun, Jiazhi; Zhou, Shufeng; Wan, Chunling; Qin, Shengying; Li, Can; He, Lin; Yang, Lun

    2013-01-01

    Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI). However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap). Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1) some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2) in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects. PMID:24244130

  6. Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

    PubMed

    Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

    2015-07-15

    Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html.

  7. COMPARTMENTALIZED CANCER DRUG DISCOVERY TARGETING MITOCHONDRIAL Hsp90 CHAPERONES

    PubMed Central

    Kang, Byoung Heon; Altieri, Dario C.

    2009-01-01

    There is a plethora of attractive drug targets in cancer, but their therapeutic exploitation proved more difficult than expected, and only rarely truly successful. One possibility not often considered in drug discovery is that cancer signaling pathways are not randomly arranged in cells, but orchestrated in specialized subcellular compartments. The identification of Heat Shock Protein-90 (Hsp90) chaperones in mitochondria of tumors, but not most normal tissues, provides an example of a compartmentalized network of cell survival, opening fresh prospects for novel, subcellularly-targeted cancer drug discovery. PMID:19648961

  8. Drug targeting systems for cancer therapy: nanotechnological approach.

    PubMed

    Tigli Aydin, R Seda

    2015-01-01

    Progress in cancer treatment remains challenging because of the great nature of tumor cells to be drug resistant. However, advances in the field of nanotechnology have enabled the delivery of drugs for cancer treatment by passively and actively targeting to tumor cells with nanoparticles. Dramatic improvements in nanotherapeutics, as applied to cancer, have rapidly accelerated clinical investigations. In this review, drug-targeting systems using nanotechnology and approved and clinically investigated nanoparticles for cancer therapy are discussed. In addition, the rationale for a nanotechnological approach to cancer therapy is emphasized because of its promising advances in the treatment of cancer patients.

  9. Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

    PubMed Central

    Taylor, Christina M.; Wang, Qi; Rosa, Bruce A.; Huang, Stanley Ching-Cheng; Powell, Kerrie; Schedl, Tim; Pearce, Edward J.; Abubucker, Sahar; Mitreva, Makedonka

    2013-01-01

    Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery

  10. A Review of Computational Methods for Predicting Drug Targets.

    PubMed

    Huang, Guohua; Yan, Fengxia; Tan, Duoduo

    2016-11-14

    Drug discovery and development is not only a time-consuming and labor-intensive process but also full of risk. Identifying targets of small molecules helps evaluate safety of drugs and find new therapeutic applications. The biotechnology measures a wide variety of properties related to drug and targets from different perspectives, thus generating a large body of data. This undoubtedly provides a solid foundation to explore relationships between drugs and targets. A large number of computational techniques have recently been developed for drug target prediction. In this paper, we summarize these computational methods and classify them into structure-based, molecular activity-based, side-effect-based and multi-omics-based predictions according to the used data for inference. The multi-omics-based methods are further grouped into two types: classifier-based and network-based predictions. Furthermore,the advantages and limitations of each type of methods are discussed. Finally, we point out the future directions of computational predictions for drug targets.

  11. Large-scale Direct Targeting for Drug Repositioning and Discovery

    PubMed Central

    Zheng, Chunli; Guo, Zihu; Huang, Chao; Wu, Ziyin; Li, Yan; Chen, Xuetong; Fu, Yingxue; Ru, Jinlong; Ali Shar, Piar; Wang, Yuan; Wang, Yonghua

    2015-01-01

    A system-level identification of drug-target direct interactions is vital to drug repositioning and discovery. However, the biological means on a large scale remains challenging and expensive even nowadays. The available computational models mainly focus on predicting indirect interactions or direct interactions on a small scale. To address these problems, in this work, a novel algorithm termed weighted ensemble similarity (WES) has been developed to identify drug direct targets based on a large-scale of 98,327 drug-target relationships. WES includes: (1) identifying the key ligand structural features that are highly-related to the pharmacological properties in a framework of ensemble; (2) determining a drug’s affiliation of a target by evaluation of the overall similarity (ensemble) rather than a single ligand judgment; and (3) integrating the standardized ensemble similarities (Z score) by Bayesian network and multi-variate kernel approach to make predictions. All these lead WES to predict drug direct targets with external and experimental test accuracies of 70% and 71%, respectively. This shows that the WES method provides a potential in silico model for drug repositioning and discovery. PMID:26155766

  12. Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

    PubMed Central

    Davis, Thomas P.

    2013-01-01

    Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion–transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia. PMID:23343976

  13. Targeted drug delivery using genetically engineered diatom biosilica.

    PubMed

    Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

    2015-11-10

    The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

  14. Nuclear receptors: emerging drug targets for parasitic diseases.

    PubMed

    Wang, Zhu; Schaffer, Nathaniel E; Kliewer, Steven A; Mangelsdorf, David J

    2017-02-06

    Parasitic worms infect billions of people worldwide. Current treatments rely on a small group of drugs that have been used for decades. A shortcoming of these drugs is their inability to target the intractable infectious stage of the parasite. As well-known therapeutic targets in mammals, nuclear receptors have begun to be studied in parasitic worms, where they are widely distributed and play key roles in governing metabolic and developmental transcriptional networks. One such nuclear receptor is DAF-12, which is required for normal nematode development, including the all-important infectious stage. Here we review the emerging literature that implicates DAF-12 and potentially other nuclear receptors as novel anthelmintic targets.

  15. Molecular approaches to target discovery:--evaluating targets for anti-tuberculosis drug discovery programmes.

    PubMed

    Balganesh, T S; Furr, B J A

    2007-06-01

    Selection of appropriate targets for launching antituberculosis drug discovery programmes is challenging. This challenge is magnified by the limited repertoire of 'validated targets' and the paucity of clinically successful drugs. However, continued understanding of the biology of the microbe and its interaction with the host has enabled detailed evaluation of several interesting pathways and novel targets. The value of a target that is suitable for antituberculosis drug discovery needs to be defined not only in the context of its 'essentiality' for survival in vitro but also against a variety of properties relevant to activities in the drug discovery process, e.g.; selectivity, vulnerability, suitability for structural studies, ability to monitor inhibition in whole cells etc. It is also rarely feasible to obtain all the relevant information on the target prior to the launch of a discovery programme. Thus, there is a continuous confidence-building exercise on the validity of a target. Several novel approaches have enabled exploitation of the mycobacterial genome and prioritisation of putative targets; the concept of 'sterilisation' is now being evaluated not only through the availability of structurally diverse probe compounds but also by the ability to characterise metabolic pathways in vivo. The impact of the current knowledge base on the different facets of 'target validation' relevant to antituberculosis drug discovery is discussed in this article with emphasis on developing appropriate matrix systems to prioritise them. The article also discusses the influence of lead generation approaches with specific reference to antibacterial drug discovery.

  16. Targeting efflux pumps to overcome antifungal drug resistance.

    PubMed

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  17. Nanostructured porous Si-based nanoparticles for targeted drug delivery

    PubMed Central

    Shahbazi, Mohammad-Ali; Herranz, Barbara; Santos, Hélder A.

    2012-01-01

    One of the backbones in nanomedicine is to deliver drugs specifically to unhealthy cells. Drug nanocarriers can cross physiological barriers and access different tissues, which after proper surface biofunctionalization can enhance cell specificity for cancer therapy. Recent developments have highlighted the potential of mesoporous silica (PSiO2) and silicon (PSi) nanoparticles for targeted drug delivery. In this review, we outline and discuss the most recent advances on the applications and developments of cancer therapies by means of PSiO2 and PSi nanomaterials. Bio-engineering and fine tuning of anti-cancer drug vehicles, high flexibility and potential for sophisticated release mechanisms make these nanostructures promising candidates for “smart” cancer therapies. As a result of their physicochemical properties they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting. The main emphasis of this review will be on the in vitro and in vivo studies. PMID:23507894

  18. Proteomic profiling predicts drug response to novel targeted anticancer therapeutics.

    PubMed

    Lin, Fan; Li, Zilin; Hua, Yunfen; Lim, Yoon Pin

    2016-01-01

    Most recently approved anti-cancer drugs by the US FDA are targeted therapeutic agents and this represents an important trend for future anticancer therapy. Unlike conventional chemotherapy that rarely considers individual differences, it is crucial for targeted therapies to identify the beneficial subgroup of patients for the treatment. Currently, genomics and transcriptomics are the major 'omic' analytics used in studies of drug response prediction. However, proteomic profiling excels both in its advantages of directly detecting an instantaneous dynamic of the whole proteome, which contains most current diagnostic markers and therapeutic targets. Moreover, proteomic profiling improves understanding of the mechanism for drug resistance and helps finding optimal combination therapy. This article reviews the recent success of applications of proteomic analytics in predicting the response to targeted anticancer therapeutics, and discusses the potential avenues and pitfalls of proteomic platforms and techniques used most in the field.

  19. Revisiting AMPA receptors as an antiepileptic drug target.

    PubMed

    Rogawski, Michael A

    2011-03-01

    In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As drugs became available that selectively target AMPA receptors, it was possible to demonstrate that AMPA receptor antagonists have powerful antiseizure activity in in vitro and in vivo models. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagonist perampanel, are once again focusing attention on AMPA receptors as a drug target for epilepsy therapy.

  20. Drug targeting by macromolecules without recognition unit?

    PubMed

    Hudecz, Ferenc; Reményi, Judit; Szabó, Rita; Kóczán, György; Mezo, Gábor; Kovács, Péter; Gaál, Dezso

    2003-01-01

    his review will summarize available information on the ability of macromolecular conjugates containing no specific recognition motifs to deliver anthracyclines (daunomycin, adriamycin) or methotrexate to target cells such as tumour cells or macrophages. Conjugates with natural (proteins, DNA, carbohydrates) and synthetic macromolecules (linear and branched chain poly-alpha-amino acids, non-biodegradable DIVEMA, HPMA etc.) will be reviewed. Experimental data from several laboratories indicate that these conjugates are taken up by cells mainly by fluid-phase or adsorptive endocytosis. It is believed that these processes do not involve 'specific receptors'. Two examples of methotrexate and daunomycin conjugates will be discussed to show the effect of the chemical structure of branched chain polypeptides on the uptake and antitumour or antiparasitic (Leishmania donovani infection) efficacy of conjugates.

  1. Aquaporins: important but elusive drug targets

    PubMed Central

    Verkman, Alan S.; Anderson, Marc O.; Papadopoulos, Marios C.

    2014-01-01

    The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators. PMID:24625825

  2. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening.

    PubMed

    Park, Yoon-Dong; Sun, Wei; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Wang, Amy; Xu, Xin; Meng, Zhaojin; Zhou, Ming; Tawa, Gregory J; Dehdashti, Jean; Zheng, Wei; Henderson, Christina M; Zelazny, Adrian M; Williamson, Peter R

    2016-08-02

    Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus

  3. Aquaporins as targets for drug discovery.

    PubMed

    Frigeri, Antonio; Nicchia, Grazia Paola; Svelto, Maria

    2007-01-01

    The intracellular hydric balance is an essential process of mammalian cells. The water movement across cell membranes is driven by osmotic and hydrostatic forces and the speed of this process is dependent on the presence of specific aquaporin water channels. Since the molecular identification of the first water channel, AQP1, by Peter Agre's group, 13 homologous members have been found in mammals with varying degree of homology. The fundamental importance of these proteins in all living cells is suggested by their genetic conservation in eukaryotic organisms through plants to mammals. A number of recent studies have revealed the importance of mammalian AQPs in both physiology and pathophysiology and have suggested that pharmacological modulation of aquaporins expression and activity may provide new tools for the treatment of variety of human disorders, such as brain edema, glaucoma, tumour growth, congestive heart failure and obesity in which water and small solute transport may be involved. This review will highlight the physiological role and the pathological involvement of AQPs in mammals and the potential use of some recent therapeutic approaches, such as RNAi and immunotherapy, for AQP-related diseases. Furthermore, strategies that can be developed for the discovery of selective AQP-drugs will be introduced and discussed.

  4. Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

    PubMed

    Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

    2014-10-01

    There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Canonical and new generation anticancer drugs also target energy metabolism.

    PubMed

    Rodríguez-Enríquez, Sara; Gallardo-Pérez, Juan Carlos; Hernández-Reséndiz, Ileana; Marín-Hernández, Alvaro; Pacheco-Velázquez, Silvia C; López-Ramírez, Sayra Y; Rumjanek, Franklin D; Moreno-Sánchez, Rafael

    2014-07-01

    Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in-depth analysis of the side effects of several currently used canonical (platin-based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment.

  6. Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs

    PubMed Central

    Dwyer, Donard S.; Aamodt, Eric; Cohen, Bruce; Buttner, Edgar A.

    2014-01-01

    Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts. PMID:25120487

  7. Discovery of peptide drug carrier candidates for targeted multi-drug delivery into prostate cancer cells.

    PubMed

    Bashari, O; Redko, B; Cohen, A; Luboshits, G; Gellerman, G; Firer, M A

    2017-09-06

    Metastatic castration-resistant prostate cancer (mCRPC) remains essentially incurable. Targeted Drug Delivery (TDD) systems may overcome the limitations of current mCRPC therapies. We describe the use of strict criteria to isolate novel prostate cancer cell targeting peptides that specifically deliver drugs into target cells. Phage from a libraries displaying 7mer peptides were exposed to PC-3 cells and only internalized phage were recovered. The ability of these phage to internalize into other prostate cancer cells (LNCaP, DU-145) was validated. The displayed peptides of selected phage clones were synthesized and their specificity for target cells was validated in vitro and in vivo. One peptide (P12) which specifically targeted PC-3 tumors in vivo was incorporated into mono-drug (Chlorambucil, Combretastatin or Camptothecin) and dual-drug (Chlorambucil/Combretastatin or Chlorambucil/Camptothecin) PDCs and the cytotoxic efficacy of these conjugates for target cells was tested. Conjugation of P12 into dual-drug PDCs allowed discovery of new drug combinations with synergistic effects. The use of strict selection criteria can lead to discovery of novel peptides for use as drug carriers for TDD. PDCs represent an effective alternative to current modes of free drug chemotherapy for prostate cancer. Copyright © 2017. Published by Elsevier B.V.

  8. Nanoparticle-based targeted drug delivery

    PubMed Central

    Singh, Rajesh; Lillard, James W.

    2009-01-01

    Nanotechnology could be defined as the technology that has allowed for the control, manipulation, study, and manufacture of structures and devices in the “nanometer” size range. These nano-sized objects, e.g., “nanoparticles”, take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved solubility, and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnology for the biologist and discusses the attributes of our novel XPclad© nanoparticle formulation that has shown efficacy in treating solid tumors, for single dose vaccination, and oral delivery of therapeutic proteins. PMID:19186176

  9. MMPs: a novel drug target for schizophrenia.

    PubMed

    Chopra, Kanwaljit; Baveja, Ankita; Kuhad, Anurag

    2015-01-01

    Schizophrenia, a multifactorial disorder, is associated with dopaminergic hyperactivity, dysregulated glutamatergic neurotransmission, neuroinflammation and extracellular matrix (ECM) disturbances. MMPs, a group of structurally related proteolytic enzymes, are responsible for remodeling of ECM that maintains synaptic functions and blood-brain barrier (BBB) patency. Overstimulation of MMPs by neuroinflammation triggers ECM abnormalities that directly or indirectly alter neuronal functions like synaptic plasticity and damage to BBB. MMP-mediated ECM abnormality plays a central role in the pathogenesis of schizophrenia. The current review discusses the mechanistic involvement of MMPs in the pathogenesis of schizophrenia and briefly gives an overview on the recent studies on various MMP modulators. Overexpression of MMPs and imbalance between MMP versus tissue inhibitors of metalloproteinase are associated with various ECM disturbances in the schizophrenic brain. Therefore, MMPs can be projected as potential therapeutic target for treatment and/or prevention of positive, negative and cognitive symptoms of schizophrenia. From past decade, scientific community is focusing on broad spectrum MMP modulators as potential therapeutic moieties for prevention of plethora of neurological, cardiovascular and pulmonary diseases. In future, specific MMP modulators should be tailored to regulate ECM integrity and explored for their pharmacotherapeutic potential in schizophrenia.

  10. The Sodium Channel as a Target for Local Anesthetic Drugs

    PubMed Central

    Fozzard, Harry A.; Sheets, Michael F.; Hanck, Dorothy A.

    2011-01-01

    Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA), which have been used for local and regional anesthesia and for excitatory problems such as epilepsy and cardiac arrhythmia. These drugs are prototypes for new analgesic drugs. The drug-binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated) position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development. PMID:22053156

  11. [Progress of mesoporous silica nanoparticles in targeting drug delivery system of antitumor drug].

    PubMed

    Zhang, Hong-min; Mo, Shu; Liu, Xiao-qian; Han, Fu-man; Wang, Jin-yu; Wang, Zhi-min

    2015-09-01

    Currently, chemotherapy is one of the main therapy for cancer. But the traditional antitumor drugs are systemic distribution in vivo, they are difficult to achieve an effective drug concentration in the tumor tissue and don't have the ability to distinguish normal cells and tumor cells by themselves, that cause systemic toxicity easily and can not meet the clinical needs. With the research on mesoporous silica nanoparticles (MSNs) deepening, more and more attention in the drug delivery system have been payed to in recent years, because of its unique physicochemical structure characteristics, it has the effect on specific targets, directly inhibits the tumor cell growth, reduces the side effects to normal cells, tissues and organs and can be long-term medication, etc. It is expected to be excellent carriers of antitumor drugs. MSNs application in the field of cancer treatment has now become a hot research field of medicine. In this paper, the latest research about MSNs in antitumor drugs targeting delivery system from 2008 to 2015 is summarized, including the application of MSNs separately in antitumor drug targeting, passive targeting, active targeting, physical or chemical conditions response targeting and other compound targeting drug delivery system. We expect it to provide a reference to the toxicity reducing and efficacy enhancing and further development of chemical medicine, natural medicine and monomeric compound of chinese herbal medicine.

  12. Membrane Transporters: Structure, Function and Targets for Drug Design

    NASA Astrophysics Data System (ADS)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  13. Prostate Cancer Relevant Antigens and Enzymes for Targeted Drug Delivery

    PubMed Central

    Barve, Ashutosh; Jin, Wei; Cheng, Kun

    2014-01-01

    Chemotherapy is one of the most widely used approaches in combating advanced prostate cancer, but its therapeutic efficacy is usually insufficient due to lack of specificity and associated toxicity. Lack of targeted delivery to prostate cancer cells is also the primary obstacles in achieving feasible therapeutic effect of other promising agents including peptide, protein, and nucleic acid. Consequently, there remains a critical need for strategies to increase the selectivity of anti-prostate cancer agents. This review will focus on various prostate cancer-specific antigens and enzymes that could be exploited for prostate cancer targeted drug delivery. Among various targeting strategies, active targeting is the most advanced approach to specifically deliver drugs to their designated cancer cells. In this approach, drug carriers are modified with targeting ligands that can specifically bind to prostate cancer-specific antigens. Moreover, there are several specific enzymes in the tumor microenvironment of prostate cancer that can be exploited for stimulus-responsive drug delivery systems. These systems can specifically release the active drug in the tumor microenvironment of prostate cancer, leading to enhanced tumor penetration efficiency. PMID:24878184

  14. Drug-target interaction prediction from PSSM based evolutionary information.

    PubMed

    Mousavian, Zaynab; Khakabimamaghani, Sahand; Kavousi, Kaveh; Masoudi-Nejad, Ali

    2016-01-01

    The labor-intensive and expensive experimental process of drug-target interaction prediction has motivated many researchers to focus on in silico prediction, which leads to the helpful information in supporting the experimental interaction data. Therefore, they have proposed several computational approaches for discovering new drug-target interactions. Several learning-based methods have been increasingly developed which can be categorized into two main groups: similarity-based and feature-based. In this paper, we firstly use the bi-gram features extracted from the Position Specific Scoring Matrix (PSSM) of proteins in predicting drug-target interactions. Our results demonstrate the high-confidence prediction ability of the Bigram-PSSM model in terms of several performance indicators specifically for enzymes and ion channels. Moreover, we investigate the impact of negative selection strategy on the performance of the prediction, which is not widely taken into account in the other relevant studies. This is important, as the number of non-interacting drug-target pairs are usually extremely large in comparison with the number of interacting ones in existing drug-target interaction data. An interesting observation is that different levels of performance reduction have been attained for four datasets when we change the sampling method from the random sampling to the balanced sampling.

  15. Progress in functional genomics approaches to antifungal drug target discovery.

    PubMed

    De Backer, Marianne D; Van Dijck, Patrick

    2003-10-01

    Antifungal drug discovery is starting to benefit from the enormous advances in the genomics field, which have occurred in the past decade. As traditional drug screening on existing targets is not delivering the long-awaited potent antifungals, efforts to use novel genetics and genomics-based strategies to aid in the discovery of novel drug targets are gaining increased importance. The current paradigm in antifungal drug target discovery focuses on basically two main classes of targets to evaluate: genes essential for viability and virulence or pathogenicity factors. Here we report on recent advances in genetics and genomics-based technologies that will allow us not only to identify and validate novel fungal drug targets, but hopefully in the longer run also to discover potent novel therapeutic agents. Fungal pathogens have typically presented significant obstacles when subjected to genetics, but the creativity of scientists in the anti-infectives field and the cross-talk with scientists in other areas is now yielding exciting new tools and technologies to tackle the problem of finding potent, specific and non-toxic antifungal therapeutics.

  16. Pharmacological Validation of Trypanosoma brucei Phosphodiesterases as Novel Drug Targets

    PubMed Central

    de Koning, Harry P.; Gould, Matthew K.; Sterk, Geert Jan; Tenor, Hermann; Kunz, Stefan; Luginbuehl, Edith; Seebeck, Thomas

    2012-01-01

    The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets. PMID:22291195

  17. Exploiting EPR in polymer drug conjugate delivery for tumor targeting.

    PubMed

    Modi, Sweta; Prakash Jain, Jay; Domb, A J; Kumar, Neeraj

    2006-01-01

    Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.

  18. Liposomes and nanotechnology in drug development: focus on neurological targets

    PubMed Central

    Ramos-Cabrer, Pedro; Campos, Francisco

    2013-01-01

    Neurological diseases represent a medical, social, and economic problem of paramount importance in developed countries. Although their etiology is generally known, developing therapeutic interventions for the central nervous system is challenging due to the impermeability of the blood–brain barrier. Thus, the fight against neurological diseases usually struggles “at the gates” of the brain. Flooding the bloodstream with drugs, where only a minor fraction reaches its target therapeutic site, is an inefficient, expensive, and dangerous procedure, because of the risk of side effects at nontargeted sites. Currently, advances in the field of nanotechnology have enabled development of a generation of multifunctional molecular platforms that are capable of transporting drugs across the blood–brain barrier, targeting specific cell types or functional states within the brain, releasing drugs in a controlled manner, and enabling visualization of processes in vivo using conventional imaging systems. The marriage between drug delivery and molecular imaging disciplines has resulted in a relatively new discipline, known as theranostics, which represents the basis of the concept of personalized medicine. In this study, we review the concepts of the blood–brain barrier and the strategies used to traverse/bypass it, the role of nanotechnology in theranostics, the wide range of nanoparticles (with emphasis on liposomes) that can be used as stealth drug carriers, imaging probes and targeting devices for the treatment of neurological diseases, and the targets and targeting strategies envisaged in the treatment of different types of brain pathology. PMID:23486739

  19. Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform

    NASA Astrophysics Data System (ADS)

    Li, Yanan; Yang, Yinlong; An, Feifei; Liu, Zhuang; Zhang, Xiujuan; Zhang, Xiaohong

    2013-01-01

    A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines.

  20. Pharmaceutical approaches to colon targeted drug delivery systems.

    PubMed

    Chourasia, M K; Jain, S K

    2003-01-01

    Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides. To achieve successful colonic delivery, a drug needs to be protected from absorption and /or the environment of the upper gastrointestinal tract (GIT) and then be abruptly released into the proximal colon, which is considered the optimum site for colon-targeted delivery of drugs. Colon targeting is naturally of value for the topical treatment of diseases of colon such as Chron's diseases, ulcerative colitis, colorectal cancer and amebiasis. Peptides, proteins, oligonucleotides and vaccines pose potential candidature for colon targeted drug delivery. The various strategies for targeting orally administered drugs to the colon include covalent linkage of a drug with a carrier, coating with pH-sensitive polymers, formulation of timed released systems, exploitation of carriers that are degraded specifically by colonic bacteria, bioadhesive systems and osmotic controlled drug delivery systems. Various prodrugs (sulfasalazine, ipsalazine, balsalazine and olsalazine) have been developed that are aimed to deliver 5-amino salicylic acid (5-ASA) for localized chemotherapy of inflammatory bowl disease (IBD). Microbially degradable polymers especially azo crosslinked polymers have been investigated for use in targeting of drugs to colon. Certain plant polysaccharides such as amylose, inulin, pectin and guar gum remains unaffected in the presence of gastrointestinal enzymes and pave the way for the formulation of colon targeted drug delivery systems. The concept of using pH as a rigger to release a drug in the colon is based on the pH conditions that vary continuously

  1. Targeting the latest hallmark of cancer: another attempt at 'magic bullet' drugs targeting cancers' metabolic phenotype.

    PubMed

    Cuperlovic-Culf, M; Culf, A S; Touaibia, M; Lefort, N

    2012-10-01

    The metabolism of tumors is remarkably different from the metabolism of corresponding normal cells and tissues. Metabolic alterations are initiated by oncogenes and are required for malignant transformation, allowing cancer cells to resist some cell death signals while producing energy and fulfilling their biosynthetic needs with limiting resources. The distinct metabolic phenotype of cancers provides an interesting avenue for treatment, potentially with minimal side effects. As many cancers show similar metabolic characteristics, drugs targeting the cancer metabolic phenotype are, perhaps optimistically, expected to be 'magic bullet' treatments. Over the last few years there have been a number of potential drugs developed to specifically target cancer metabolism. Several of these drugs are currently in clinical and preclinical trials. This review outlines examples of drugs developed for different targets of significance to cancer metabolism, with a focus on small molecule leads, chemical biology and clinical results for these drugs.

  2. Active Targeted Drug Delivery for Microbes Using Nano-Carriers

    PubMed Central

    Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

  3. The role of acoustofluidics in targeted drug delivery

    PubMed Central

    Bose, Nilanjana; Zhang, Xunli; Maiti, Tapas K.; Chakraborty, Suman

    2015-01-01

    With the fast development of acoustic systems in clinical and therapeutic applications, acoustically driven microbubbles have gained a prominent role as powerful tools to carry, transfer, direct, and target drug molecules in cells, tissues, and tumors in the expanding fields of targeted drug delivery and gene therapy. The aim of the present study is to establish a biocompatible acoustic microfluidic system and to demonstrate the generation of an acoustic field and its effects on microbubbles and biological cells in the microfluidic system. The acoustic field creates non-linear oscillations of the microbubble-clusters, which results in generation of shear stress on cells in such microsystems. This effectively helps in delivering extracellular probes in living cells by sonoporation. The sonoporation is investigated under the combined effects of acoustic stress and hydrodynamic stress during targeted drug and gene delivery. PMID:26339329

  4. [The new era of epithelium-targeted drug development].

    PubMed

    Shimizu, Yoshimi; Nagase, Shotaro; Yagi, Kiyohito; Kondoh, Masuo

    2014-01-01

    Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development.

  5. Adenosine receptors as drug targets — what are the challenges?

    PubMed Central

    Chen, Jiang-Fan; Eltzschig, Holger K.; Fredholm, Bertil B.

    2014-01-01

    Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges. PMID:23535933

  6. Ion channels and drug transporters as targets for anthelmintics

    PubMed Central

    Greenberg, Robert M.

    2014-01-01

    Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance. PMID:25554739

  7. Drugs That Target Dynamic Microtubules: A New Molecular Perspective

    PubMed Central

    Stanton, Richard A.; Gernert, Kim M.; Nettles, James H.; Aneja, Ritu

    2011-01-01

    Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work. PMID:21381049

  8. Ion channels and drug transporters as targets for anthelmintics.

    PubMed

    Greenberg, Robert M

    2014-12-01

    Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

  9. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    PubMed Central

    Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

    2015-01-01

    Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  10. Critical parameters in targeted drug development: the pharmacological audit trail.

    PubMed

    Banerji, Udai; Workman, Paul

    2016-08-01

    The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. The questions asked in the PhAT should be viewed as a continuum and not used in isolation. Different drug development programmes derive different types of benefit from these questions. The PhAT is critical in making go-no-go decisions in the development of currently studied drugs and will continue to be relevant to discovery and development of future generations of anticancer agents.

  11. Target-Independent Prediction of Drug Synergies Using Only Drug Lipophilicity

    PubMed Central

    2015-01-01

    Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds (“drugs”) previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms. PMID:25026390

  12. Members of FOX family could be drug targets of cancers.

    PubMed

    Wang, Jinhua; Li, Wan; Zhao, Ying; Kang, De; Fu, Weiqi; Zheng, Xiangjin; Pang, Xiaocong; Du, Guanhua

    2017-08-19

    FOX families play important roles in biological processes, including metabolism, development, differentiation, proliferation, apoptosis, migration, invasion and longevity. Here we are focusing on roles of FOX members in cancers, FOX members and drug resistance, FOX members and stem cells. Finally, FOX members as drug targets of cancer treatment were discussed. Future perspectives of FOXC1 research were described in the end. Copyright © 2017. Published by Elsevier Inc.

  13. New therapeutic targets and drugs for the treatment of asthma.

    PubMed

    Alves, Mateus Feitosa; da Fonsec, Diogo Vilar; de Melo, Sílvia Adelaide Linhares; Scotti, Marcus Tullius; Scotti, Luciana; Dos Santos, Sócrates Golzio; de Fátima Formiga Melo Diniz, Margareth

    2017-09-27

    Asthma is an inflammatory disease which affects millions of people worldwide. Therefore, it is necessary search for new sources of therapies for the treatment of these patients in order to improve their quality of life. From content analysis of new therapeutic targets literature, there are various targets and drugs reported as promising for treatment asthma. Interleukins involved in inflammatory processes are often presented as candidate targets for new drugs. The action of such therapeutics would not only affect interleukins, but also in their receptors. Ligustrazine and SP600125 are small molecules and compounds and lebrikizumab, benralizumab and dupilumab are large molecule antibodies investigational product, though are being considered as novel agents for the pharmacotherapy of asthma. Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. The lebrikizumab inhibit interleukins 13 and dupilumab is directed against IL-4Ra and hence inhibits activation of the receptor by IL-4 and IL-13. SP600125 and ligustrazine drugs act on the important inflammatory pathway, MAPK. Therefore, through this research, we can see advances in the search for new targets and promising drugs to treat asthma. It is expected that these new drug candidates will eventually be approved and marketed so that asthma patients can use them and enhance their quality of life. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Identifying problematic drugs based on the characteristics of their targets

    PubMed Central

    Lopes, Tiago J. S.; Shoemaker, Jason E.; Matsuoka, Yukiko; Kawaoka, Yoshihiro; Kitano, Hiroaki

    2015-01-01

    Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/. PMID:26388775

  15. Target mRNA inhibition by oligonucleotide drugs in man

    PubMed Central

    Lightfoot, Helen L.; Hall, Jonathan

    2012-01-01

    Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this field. PMID:22989709

  16. Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery.

    PubMed

    Płocinska, Renata; Korycka-Machala, Malgorzata; Plocinski, Przemyslaw; Dziadek, Jaroslaw

    2017-06-16

    Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors - the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and

  17. Mesoporous silica nanoparticles in target drug delivery system: A review

    PubMed Central

    Bharti, Charu; Nagaich, Upendra; Pal, Ashok Kumar; Gulati, Neha

    2015-01-01

    Due to lack of specification and solubility of drug molecules, patients have to take high doses of the drug to achieve the desired therapeutic effects for the treatment of diseases. To solve these problems, there are various drug carriers present in the pharmaceuticals, which can used to deliver therapeutic agents to the target site in the body. Mesoporous silica materials become known as a promising candidate that can overcome above problems and produce effects in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles (MSNs) are widely used as a delivery reagent because silica possesses favorable chemical properties, thermal stability, and biocompatibility. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release of the target site. The properties of mesoporous, including pore size, high drug loading, and porosity as well as the surface properties, can be altered depending on additives used to prepare MSNs. Active surface enables functionalization to changed surface properties and link therapeutic molecules. They are used as widely in the field of diagnosis, target drug delivery, bio-sensing, cellular uptake, etc., in the bio-medical field. This review aims to present the state of knowledge of silica containing mesoporous nanoparticles and specific application in various biomedical fields. PMID:26258053

  18. Focus on flaviviruses: current and future drug targets

    PubMed Central

    Geiss, Brian J; Stahla, Hillary; Hannah, Amanda M; Gari, Harmid H; Keenan, Susan M

    2009-01-01

    Background Infection by mosquito-borne flaviviruses (family Flaviviridae) is increasing in prevalence worldwide. The vast global, social and economic impact due to the morbidity and mortality associated with the diseases caused by these viruses necessitates therapeutic intervention. There is currently no effective clinical treatment for any flaviviral infection. Therefore, there is a great need for the identification of novel inhibitors to target the virus lifecycle. Discussion In this article, we discuss structural and nonstructural viral proteins that are the focus of current target validation and drug discovery efforts. Both inhibition of essential enzymatic activities and disruption of necessary protein–protein interactions are considered. In addition, we address promising new targets for future research. Conclusion As our molecular and biochemical understanding of the flavivirus life cycle increases, the number of targets for antiviral therapeutic discovery grows and the possibility for novel drug discovery continues to strengthen. PMID:20165556

  19. Existing drugs and their application in drug discovery targeting cancer stem cells.

    PubMed

    Lv, Junfang; Shim, Joong Sup

    2015-09-01

    Despite standard cancer therapies such as chemotherapy and targeted therapy have shown some efficacies, the cancer in many cases eventually relapses and metastasizes upon stopping the treatment. There is a small subpopulation of cancer cells within tumor, with specific characters similar to those found in stem cells. This group of cancer cells is known as tumor-initiating or cancer stem cells (CSCs), which have an ability to self-renew and give rise to cancer cell progeny. CSCs are related with drug resistance, metastasis and relapse of cancer, hence emerging as a crucial drug target for eliminating cancer. Rapid advancement of CSC biology has enabled researchers to isolate and culture CSCs in vitro, making the cells amenable to high-throughput drug screening. Recently, drug repositioning, which utilizes existing drugs to develop potential new indications, has been gaining popularity as an alternative approach for the drug discovery. As existing drugs have favorable bioavailability and safety profiles, drug repositioning is now actively exploited for prompt development of therapeutics for many serious diseases, such as cancer. In this review, we will introduce latest examples of attempted drug repositioning targeting CSCs and discuss potential use of the repositioned drugs for cancer therapy.

  20. A smart multifunctional drug delivery nanoplatform for targeting cancer cells

    NASA Astrophysics Data System (ADS)

    Hoop, M.; Mushtaq, F.; Hurter, C.; Chen, X.-Z.; Nelson, B. J.; Pané, S.

    2016-06-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of

  1. External triggering and triggered targeting strategies for drug delivery

    NASA Astrophysics Data System (ADS)

    Wang, Yanfei; Kohane, Daniel S.

    2017-06-01

    Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field.

  2. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    DTIC Science & Technology

    2015-04-01

    mammalian cycle. Inhibiting this step can block malaria at an early step. However, few anti-malar ials target l iver infection by sporozo ites. Our...step of the Plasmodium mammalian cycle. Inhibiting this step can block malaria at an early step. However, few anti-malarials target liver infection...intrahepatic development 2. Keywords Plasmodium, sporozoites, liver infection, kinase, drugs, malaria 3. Accomplishments • What were the major

  3. Structure-based methods for predicting target mutation-induced drug resistance and rational drug design to overcome the problem.

    PubMed

    Hao, Ge-Fei; Yang, Guang-Fu; Zhan, Chang-Guo

    2012-10-01

    Drug resistance has become one of the biggest challenges in drug discovery and/or development and has attracted great research interests worldwide. During the past decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance. In this article we review recent advances in development of computational methods for target mutation-induced drug resistance prediction and strategies for rational design of novel inhibitors that could be effective against the possible drug-resistant mutants of the target.

  4. Increasing the Structural Coverage of Tuberculosis Drug Targets

    PubMed Central

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

    2015-01-01

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. PMID:25613812

  5. Increasing the structural coverage of tuberculosis drug targets

    DOE PAGES

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; ...

    2014-12-19

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

  6. Increasing the structural coverage of tuberculosis drug targets

    SciTech Connect

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

    2014-12-19

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

  7. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    DTIC Science & Technology

    2012-09-01

    dendrimers and its applications for drug delivery .............................................. 19 2.1 Synthesis of degradable polyester dendrimers for...24 2.3 Dendrimer /lipid nanoassembly as “cluster bomb” for cascade tumor penetration...reversal peptide as nuclear-targeted drug carriers. Moreover, we synthesized a series of degradable dendrimers and applied such dendrimers to

  8. Sexually transmitted diseases putative drug target database: a comprehensive database of putative drug targets of pathogens identified by comparative genomics.

    PubMed

    Malipatil, Vijayakumari; Madagi, Shivkumar; Bhattacharjee, Biplab

    2013-01-01

    Sexually transmitted diseases (STD) are the serious public health problems and also impose a financial burden on the economy. Sexually transmitted infections are cured with single or multiple antibiotics. However, in many cases the organism showed persistence even after treatment. In the current study, the set of druggable targets in STD pathogens have been identified by comparative genomics. The subtractive genomics scheme exploits the properties of non-homology, essentiality, membrane localization and metabolic pathway uniqueness in identifying the drug targets. To achieve the effective use of data and to understand properties of drug target under single canopy, an integrated knowledge database of drug targets in STD bacteria was created. Data for each drug targets include biochemical pathway, function, cellular localization, essentiality score and structural details. The proteome of STD pathogens yielded 44 membrane associated proteins possessing unique metabolic pathways when subjected to the algorithm. The database can be accessed at http://biomedresearchasia.org/index.html. Diverse data merged in the common framework of this database is expected to be valuable not only for basic studies in clinical bioinformatics, but also for basic studies in immunological, biotechnological and clinical fields.

  9. Sirtuins as potential drug targets for metablic diseases

    USDA-ARS?s Scientific Manuscript database

    Recent studies of the sirtuin family of proteins, which possess NAD+/-dependent deacetylase and ADP ribosyltransferase activities, indicate that they regulate many biological functions, such as longevity and metabolism. These findings also suggest that sirtuins might serve as valuable drug targets f...

  10. Mitochondrial chaperones may be targets for anti-cancer drugs

    Cancer.gov

    Scientists at NCI have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but sc

  11. Progress in brain targeting drug delivery system by nasal route.

    PubMed

    Khan, Abdur Rauf; Liu, Mengrui; Khan, Muhammad Wasim; Zhai, Guangxi

    2017-09-05

    The blood-brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct targeting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery technologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs via nasal administration. Carbopol 934p (PubChem CID: 6581) Carboxy methylcellulose (PubChem CID: 24748) Penetratin (PubChem CID: 101111470) Poly lactic-co-glycolic acid (PubChem CID: 23111554) Tween 80 (PubChem CID: 5284448). Copyright © 2017. Published by Elsevier B.V.

  12. Breakable mesoporous silica nanoparticles for targeted drug delivery.

    PubMed

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A; Robinet, Eric; De Cola, Luisa

    2016-04-07

    "Pop goes the particle". Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.

  13. Biomimetic and bioinspired nanoparticles for targeted drug delivery.

    PubMed

    Gagliardi, Mariacristina

    2017-03-01

    In drug targeting, the urgent need for more effective and less iatrogenic therapies is pushing toward a complete revision of carrier setup. After the era of 'articles used as homing systems', novel prototypes are now emerging. Newly conceived carriers are endowed with better biocompatibility, biodistribution and targeting properties. The biomimetic approach bestows such improved functional properties. Exploiting biological molecules, organisms and cells, or taking inspiration from them, drug vector performances are now rapidly progressing toward the perfect carrier. Following this direction, researchers have refined carrier properties, achieving significant results. The present review summarizes recent advances in biomimetic and bioinspired drug vectors, derived from biologicals or obtained by processing synthetic materials with a biomimetic approach.

  14. Predicting drug-target interactions using probabilistic matrix factorization.

    PubMed

    Cobanoglu, Murat Can; Liu, Chang; Hu, Feizhuo; Oltvai, Zoltán N; Bahar, Ivet

    2013-12-23

    Quantitative analysis of known drug-target interactions emerged in recent years as a useful approach for drug repurposing and assessing side effects. In the present study, we present a method that uses probabilistic matrix factorization (PMF) for this purpose, which is particularly useful for analyzing large interaction networks. DrugBank drugs clustered based on PMF latent variables show phenotypic similarity even in the absence of 3D shape similarity. Benchmarking computations show that the method outperforms those recently introduced provided that the input data set of known interactions is sufficiently large--which is the case for enzymes and ion channels, but not for G-protein coupled receptors (GPCRs) and nuclear receptors. Runs performed on DrugBank after hiding 70% of known interactions show that, on average, 88 of the top 100 predictions hit the hidden interactions. De novo predictions permit us to identify new potential interactions. Drug-target pairs implicated in neurobiological disorders are overrepresented among de novo predictions.

  15. Screening drug-target interactions with positive-unlabeled learning.

    PubMed

    Peng, Lihong; Zhu, Wen; Liao, Bo; Duan, Yu; Chen, Min; Chen, Yi; Yang, Jialiang

    2017-08-14

    Identifying drug-target interaction (DTI) candidates is crucial for drug repositioning. However, usually only positive DTIs are deposited in known databases, which challenges computational methods to predict novel DTIs due to the lack of negative samples. To overcome this dilemma, researchers usually randomly select negative samples from unlabeled drug-target pairs, which introduces a lot of false-positives. In this study, a negative sample extraction method named NDTISE is first developed to screen strong negative DTI examples based on positive-unlabeled learning. A novel DTI screening framework, PUDTI, is then designed to infer new drug repositioning candidates by integrating NDTISE, probabilities that remaining ambiguous samples belong to the positive and negative classes, and an SVM-based optimization model. We investigated the effectiveness of NDTISE on a DTI data provided by NCPIS. NDTISE is much better than random selection and slightly outperforms NCPIS. We then compared PUDTI with 6 state-of-the-art methods on 4 classes of DTI datasets from human enzymes, ion channels, GPCRs and nuclear receptors. PUDTI achieved the highest AUC among the 7 methods on all 4 datasets. Finally, we validated a few top predicted DTIs through mining independent drug databases and literatures. In conclusion, PUDTI provides an effective pre-filtering method for new drug design.

  16. Functional and mechanistic analysis of telomerase: An antitumor drug target.

    PubMed

    Chen, Yinnan; Zhang, Yanmin

    2016-07-01

    The current research on anticancer drugs focuses on exploiting particular traits or hallmarks unique to cancer cells. Telomerase, a special reverse transcriptase, has been recognized as a common factor in most tumor cells, and in turn a distinctive characteristic with respect to non-malignant cells. This feature has made telomerase a preferred target for anticancer drug development and cancer therapy. This review aims to analyze the pharmacological function and mechanism and role of telomerase in oncogenesis; to provide fundamental knowledge for research on the structure, function, and working mechanism of telomerase; to expound the role that telomerase plays in the initiation and development of tumor and its relationship with tumor cell growth, proliferation, apoptosis, and related pathway molecules; and to display potential targets of antitumor drug for inhibiting the expression, reconstitution, and trafficking of the enzyme. We therefore summarize recent advances in potential telomerase inhibitors for antitumor including natural products, synthetic small molecules, peptides and proteins, which indicate that optimizing the delivery method and drug combination could be of help in a combinatorial drug treatment for tumor. More extensive understanding of the structure, biogenesis, and mechanism of telomerase will provide invaluable information for increasing the efficiency of rational antitumor drug design. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. [Site-specific drug delivery systems. I. Colon targeted delivery].

    PubMed

    Szente, Virág; Zelkó, Romána

    2007-01-01

    Colon specific drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon like Chron's disease, ulcerative colitis, irritable bowel syndrome, cancer or infections, but also for the potential it holds for the systemic delivery of proteins (e.g. insulin) and therapeutic peptides. These systems enable the protection of healthy tissues from the side effects of drugs and the drug intake of targeted cells, as well. The formulation of colon specific drug delivery systems is of great impact in the case of diseases having circadian rhythm (midnight gerd). Such circadian rhythm release drug delivery systems are designed to provide a plasma concentration--time profile, which varies according to physiological need at different times during the dosing period, i.e., mimicking the circadian rhythm and severity/manifestation of gastric acid secretion (and/or midnight gerd). In general four primary approaches have been proposed for colon targeted delivery namely pH-dependent systems, time dependent systems, colonic microflora activated systems and prodrugs.

  18. [Development of a Drug Discovery Method Targeted to Stromal Tissue].

    PubMed

    Kamada, Haruhiko

    2016-01-01

    Several diseases are characterized by alterations in the molecular distribution of vascular structures, presenting the opportunity to use monoclonal antibodies for clinical therapies. This pharmaceutical strategy, often referred to as "vascular targeting", has promise in promoting the discovery and development of selective biological drugs to regulate angiogenesis-related diseases such as cancer. Various experimental approaches have been utilized to discover accessible vascular markers of health and disease at the protein level. Our group has developed a new chemical proteomics technology to identify and quantify accessible vascular proteins in normal organs and at disease sites. Our developed methodology relies on the perfusion of animal models with suitable ester derivatives of biotin, which react with the primary amine groups of proteins as soon as the molecules are attached. This presentation reports biomedical applications based on vascular targeting strategies, as well as methodologies that have been used to discover new vascular targets. The identification of antigens located in the stromal tissue of pathological blood vessels may provide attractive targets for the development of antibody drugs. This method will also provide an efficient discovery target that could lead to the development of novel antibody drugs.

  19. Intestinal targeting of drugs: rational design approaches and challenges.

    PubMed

    Filipski, Kevin J; Varma, Manthena V; El-Kattan, Ayman F; Ambler, Catherine M; Ruggeri, Roger B; Goosen, Theunis C; Cameron, Kimberly O

    2013-01-01

    Targeting drugs to the gastrointestinal tract has been and continues to be an active area of research. Gut-targeting is an effective means of increasing the local concentration of active substance at the desired site of action while minimizing concentrations elsewhere in the body that could lead to unwanted side-effects. Several approaches to intestinal targeting exist. Physicochemical property manipulation can drive molecules to large, polar, low absorption space or alternatively to lipophilic, high clearance space in order to minimize systemic exposure. Design of compounds that are substrates for transporters within the gastrointestinal tract, either uptake or efflux, or at the hepato-biliary interface, may help to increase intestinal concentration. Prodrug strategies have been shown to be effective particularly for colon targeting, and several different technology formulation approaches are currently being researched. This review provides examples of various approaches to intestinal targeting, and discusses challenges and areas in need of future scientific advances.

  20. Breakable mesoporous silica nanoparticles for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A.; Robinet, Eric; de Cola, Luisa

    2016-03-01

    ``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. Electronic supplementary information (ESI) available: Full experimental procedures, additional SEM and TEM images of particles, complete UV-Vis and PL-monitored characterization of the breakdown of

  1. Computational design of nanoparticle drug delivery systems for selective targeting

    NASA Astrophysics Data System (ADS)

    Duncan, Gregg A.; Bevan, Michael A.

    2015-09-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting

  2. Leveraging human genetics to guide drug target discovery.

    PubMed

    Stitziel, Nathan O; Kathiresan, Sekar

    2017-07-01

    Identifying appropriate molecular targets is a critical step in drug development. Despite many advantages, the traditional tools of observational epidemiology and cellular or animal models of disease can be misleading in identifying causal pathways likely to lead to successful therapeutics. Here, we review some favorable aspects of human genetics studies that have the potential to accelerate drug target discovery. These include using genetic studies to identify pathways relevant to human disease, leveraging human genetics to discern causal relationships between biomarkers and disease, and studying genetic variation in humans to predict the potential efficacy and safety of inhibitory compounds aimed at molecular targets. We present some examples taken from studies of plasma lipids and coronary artery disease to highlight how human genetics can accelerate therapeutics development. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Peptide drugs to target G protein-coupled receptors.

    PubMed

    Bellmann-Sickert, Kathrin; Beck-Sickinger, Annette G

    2010-09-01

    Major indications for use of peptide-based therapeutics include endocrine functions (especially diabetes mellitus and obesity), infectious diseases, and cancer. Whereas some peptide pharmaceuticals are drugs, acting as agonists or antagonists to directly treat cancer, others (including peptide diagnostics and tumour-targeting pharmaceuticals) use peptides to 'shuttle' a chemotherapeutic agent or a tracer to the tumour and allow sensitive imaging or targeted therapy. Significant progress has been made in the last few years to overcome disadvantages in peptide design such as short half-life, fast proteolytic cleavage, and low oral bioavailability. These advances include peptide PEGylation, lipidisation or multimerisation; the introduction of peptidomimetic elements into the sequences; and innovative uptake strategies such as liposomal, capsule or subcutaneous formulations. This review focuses on peptides targeting G protein-coupled receptors that are promising drug candidates or that have recently entered the pharmaceutical market.

  4. The tuberculosis drug discovery and development pipeline and emerging drug targets.

    PubMed

    Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

    2015-01-29

    The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.

  5. Carbon Nanotubes: An Emerging Drug Carrier for Targeting Cancer Cells

    PubMed Central

    Bhattacharya, Shiv Sankar; Mishra, Arun Kumar; Verma, Navneet; Verma, Anurag; Pandit, Jayanta Kumar

    2014-01-01

    During recent years carbon nanotubes (CNTs) have been attracted by many researchers as a drug delivery carrier. CNTs are the third allotropic form of carbon-fullerenes which were rolled into cylindrical tubes. To be integrated into the biological systems, CNTs can be chemically modified or functionalised with therapeutically active molecules by forming stable covalent bonds or supramolecular assemblies based on noncovalent interactions. Owing to their high carrying capacity, biocompatibility, and specificity to cells, various cancer cells have been explored with CNTs for evaluation of pharmacokinetic parameters, cell viability, cytotoxicty, and drug delivery in tumor cells. This review attempts to highlight all aspects of CNTs which render them as an effective anticancer drug carrier and imaging agent. Also the potential application of CNT in targeting metastatic cancer cells by entrapping biomolecules and anticancer drugs has been covered in this review. PMID:24872894

  6. Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies.

    PubMed

    Widmer, Nicolas; Bardin, Christophe; Chatelut, Etienne; Paci, Angelo; Beijnen, Jos; Levêque, Dominique; Veal, Gareth; Astier, Alain

    2014-08-01

    Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Cancer metabolism: new validated targets for drug discovery.

    PubMed

    Sotgia, Federica; Martinez-Outschoorn, Ubaldo E; Lisanti, Michael P

    2013-08-01

    Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of "metabolic-symbiosis" has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism, we should consider therapeutically targeting mitochondrial biogenesis and OXPHOS in epithelial cancer cells. As metabolic-symbiosis promotes drug-resistance and may represent the escape mechanism during anti-angiogenic therapy, new drugs targeting metabolic-symbiosis may also be effective in cancer patients with recurrent and advanced metastatic disease.

  8. Drug delivery and release systems for targeted tumor therapy.

    PubMed

    Böhme, David; Beck-Sickinger, Annette G

    2015-03-01

    Most toxic agents currently used for chemotherapy show a narrow therapeutic window, because of their inability to distinguish between healthy and cancer cells. Targeted drug delivery offers the possibility to overcome this issue by selectively addressing structures on the surface of cancer cells, therefore reducing undesired side effects. In this broad field, peptide-drug conjugates linked by intracellular cleavable structures have evolved as highly promising agents. They can specifically deliver toxophores to tumor cells by targeting distinct receptors overexpressed in cancer. In this review, we focus on these compounds and describe important factors to develop a highly efficient peptide-drug conjugate. The necessary properties of tumor-targeting peptides are described, and the different options for cleavable linkers used to connect toxic agents and peptides are discussed, and synthetic considerations for the introduction of these structures are reported. Furthermore, recent examples and current developments of peptide-drug conjugates are critically evaluated with a special focus on the applied linker structures and their future use in cancer therapy. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

  9. Cancer Metabolism: New Validated Targets for Drug Discovery

    PubMed Central

    Sotgia, Federica; Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.

    2013-01-01

    Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of “metabolic-symbiosis” has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism, we should consider therapeutically targeting mitochondrial biogenesis and OXPHOS in epithelial cancer cells. As metabolic-symbiosis promotes drug-resistance and may represent the escape mechanism during anti-angiogenic therapy, new drugs targeting metabolic-symbiosis may also be effective in cancer patients with recurrent and advanced metastatic disease. PMID:23896568

  10. Functionalized mesoporous silicon for targeted-drug-delivery.

    PubMed

    Tabasi, Ozra; Falamaki, Cavus; Khalaj, Zahra

    2012-10-01

    The present work concerns a preliminary step in the production of anticancer drug loaded porous silicon (PSi) for targeted-drug-delivery applications. A successful procedure for the covalent attachment of folic acid, polyethylene glycol (PEG) and doxorubicin to hydrophilic mesoporous silicon layers is presented. A systematic approach has been followed to obtain the optimal composition of the N,N'-dicyclohexylcarbodiimide (DCC)/N-hydroxysuccimide (NHS) in dimethylsulfoxide (DMSO) solution for the surface activation process of the undecylenic acid (UD) grafted molecules to take place with minimal undesired byproduct formation. The effect of reactant concentration and kind of solvent (aqueous or DMSO) on the attachment of folic acid to the activated PSi layer has been investigated. The covalent attachment of the doxorubicin molecules to the PSi layer functionalized with folic acid and PEG is discussed. The drug release kinetics as a function of pH has been studied. The functionalized PSi particles show a high cytotoxicity compared to the equivalent amount of free drug. Cell toxicity tests show clearly that the incorporation of folate molecules increases substantially the toxicity of the loaded PSi particles. Accordingly this new functionalized PSi may be considered a proper candidate for targeted drug delivery.

  11. Parasite neuropeptide biology: Seeding rational drug target selection?

    PubMed Central

    McVeigh, Paul; Atkinson, Louise; Marks, Nikki J.; Mousley, Angela; Dalzell, Johnathan J.; Sluder, Ann; Hammerland, Lance; Maule, Aaron G.

    2011-01-01

    The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components – putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths. PMID:24533265

  12. Computational Discovery of Putative Leads for Drug Repositioning through Drug-Target Interaction Prediction

    PubMed Central

    2016-01-01

    De novo experimental drug discovery is an expensive and time-consuming task. It requires the identification of drug-target interactions (DTIs) towards targets of biological interest, either to inhibit or enhance a specific molecular function. Dedicated computational models for protein simulation and DTI prediction are crucial for speed and to reduce the costs associated with DTI identification. In this paper we present a computational pipeline that enables the discovery of putative leads for drug repositioning that can be applied to any microbial proteome, as long as the interactome of interest is at least partially known. Network metrics calculated for the interactome of the bacterial organism of interest were used to identify putative drug-targets. Then, a random forest classification model for DTI prediction was constructed using known DTI data from publicly available databases, resulting in an area under the ROC curve of 0.91 for classification of out-of-sampling data. A drug-target network was created by combining 3,081 unique ligands and the expected ten best drug targets. This network was used to predict new DTIs and to calculate the probability of the positive class, allowing the scoring of the predicted instances. Molecular docking experiments were performed on the best scoring DTI pairs and the results were compared with those of the same ligands with their original targets. The results obtained suggest that the proposed pipeline can be used in the identification of new leads for drug repositioning. The proposed classification model is available at http://bioinformatics.ua.pt/software/dtipred/. PMID:27893735

  13. An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles

    PubMed Central

    Kishore, Golla; Kondapi, Anand Kumar

    2009-01-01

    Background Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. Methodology/Principal Findings Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25–50 ηm, which increase to 60–80 ηm upon direct loading of drug (direct-nano), and showed further increase in dimension (75–95 ηm) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression

  14. Promises and challenges of anticancer drugs that target the epigenome.

    PubMed

    Verbrugge, Inge; Johnstone, Ricky W; Bots, Michael

    2011-10-01

    The occurrence of epigenetic aberrations in cancer and their role in promoting tumorigenesis has led to the development of various small molecule inhibitors that target epigenetic enzymes. In preclinical settings, many epigenetic inhibitors demonstrate promising activity against a variety of both hematological and solid tumors. The therapeutic efficacy of those inhibitors that have entered the clinic however, is restricted predominantly to hematological malignancies. Here we outline the observed epigenetic aberrations in various types of cancer and the clinical responses to epigenetic drugs. We furthermore discuss strategies to improve the responsiveness of both hematological and solid malignancies to epigenetic drugs.

  15. Bacterial Transcription as a Target for Antibacterial Drug Development.

    PubMed

    Ma, Cong; Yang, Xiao; Lewis, Peter J

    2016-03-01

    Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  16. Bacterial Transcription as a Target for Antibacterial Drug Development

    PubMed Central

    Ma, Cong; Yang, Xiao

    2016-01-01

    SUMMARY Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

  17. Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

    PubMed

    Barneh, Farnaz; Jafari, Mohieddin; Mirzaie, Mehdi

    2016-11-01

    Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  18. Ion Channels as Drug Targets in Central Nervous System Disorders

    PubMed Central

    Waszkielewicz, A.M; Gunia, A; Szkaradek, N; Słoczyńska, K; Krupińska, S; Marona, H

    2013-01-01

    Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na+ channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 – for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Cav1.1-Cav3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs. PMID:23409712

  19. Iron Deprivation Affects Drug Susceptibilities of Mycobacteria Targeting Membrane Integrity

    PubMed Central

    Pal, Rahul; Hameed, Saif; Fatima, Zeeshan

    2015-01-01

    Multidrug resistance (MDR) acquired by Mycobacterium tuberculosis (MTB) through continuous deployment of antitubercular drugs warrants immediate search for novel targets and mechanisms. The ability of MTB to sense and become accustomed to changes in the host is essential for survival and confers the basis of infection. A crucial condition that MTB must surmount is iron limitation, during the establishment of infection, since iron is required by both bacteria and humans. This study focuses on how iron deprivation affects drug susceptibilities of known anti-TB drugs in Mycobacterium smegmatis, a “surrogate of MTB.” We showed that iron deprivation leads to enhanced potency of most commonly used first line anti-TB drugs that could be reverted upon iron supplementation. We explored that membrane homeostasis is disrupted upon iron deprivation as revealed by enhanced membrane permeability and hypersensitivity to membrane perturbing agent leading to increased passive diffusion of drug and TEM images showing detectable differences in cell envelope thickness. Furthermore, iron seems to be indispensable to sustain genotoxic stress suggesting its possible role in DNA repair machinery. Taken together, we for the first time established a link between cellular iron and drug susceptibility of mycobacteria suggesting iron as novel determinant to combat MDR. PMID:26779346

  20. Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets

    PubMed Central

    Humphries, Edward S. A.

    2015-01-01

    Potassium (K+) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K+ (KATP) channels, very few selective K+ channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K+ channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K+ channel modulators. PMID:26303307

  1. Targeted Protein Degradation: from Chemical Biology to Drug Discovery.

    PubMed

    Cromm, Philipp M; Crews, Craig M

    2017-09-21

    Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell's own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small-molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Voltage-gated Potassium Channels as Therapeutic Drug Targets

    PubMed Central

    Wulff, Heike; Castle, Neil A.; Pardo, Luis A.

    2009-01-01

    The human genome contains 40 voltage-gated potassium channels (KV) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. KV channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacological strategies for targeting KV channels with venom peptides, antibodies and small molecules and then highlights recent progress in the preclinical and clinical development of drugs targeting KV1.x, KV7.x (KCNQ), KV10.1 (EAG1) and KV11.1 (hERG) channels. PMID:19949402

  3. A review on proniosomal drug delivery system for targeted drug action

    PubMed Central

    Radha, G. V.; Rani, T. Sudha; Sarvani, B.

    2013-01-01

    Proniosomes are dry formulation of water soluble carrier particles that are coated with surfactant. They are rehydrated to form niosomal dispersion immediately before use on agitation in hot aqueous media within minutes. Proniosomes are physically stable during the storage and transport. Drug encapsulated in the vesicular structure of proniosomes prolong the existence of drug in the systematic circulation and enhances the penetration into target tissue and reduce toxicity. From a technical point of view, niosomes are promising drug carriers as they possess greater chemical stability and lack of many disadvantages associated with liposomes, such as high- cost and variable purity problems of phospholipids. The present review emphasizes on overall methods of preparation characterization and applicability of proniosomes in targeted drug action. PMID:24808669

  4. Fatty acid biosynthesis as a drug target in apicomplexan parasites.

    PubMed

    Goodman, C D; McFadden, G I

    2007-01-01

    Apicomplexan parasitic diseases impose devastating impacts on much of the world's population. The increasing prevalence of drug resistant parasites and the growing number of immuno-compromised individuals are exacerbating the problem to the point that the need for novel, inexpensive drugs is greater now than ever. Discovery of a prokaryotic, Type II fatty acid synthesis (FAS) pathway associated with the plastid-like organelle (apicoplast) of Plasmodium and Toxoplasma has provided a wealth of novel drug targets. Since this pathway is both essential and fundamentally different from the cytosolic Type I pathway of the human host, apicoplast FAS has tremendous potential for the development of parasite-specific inhibitors. Many components of this pathway are already the target for existing antibiotics and herbicides, which should significantly reduce the time and cost of drug development. Continuing interest--both in the pharmaceutical and herbicide industries--in fatty acid synthesis inhibitors proffers an ongoing stream of potential new anti-parasitic compounds. It has now emerged that not all apicomplexan parasites have retained the Type II fatty acid biosynthesis pathway. No fatty acid biosynthesis enzymes are encoded in the genome of Theileria annulata or T. parva, suggesting that fatty acid synthesis is lacking in these parasites. The human intestinal parasite Cryptosporidium parvum appears to have lost the apicoplast entirely; instead relying on an unusual cytosolic Type I FAS. Nevertheless, newly developed anti-cancer and anti-obesity drugs targeting human Type I FAS may yet prove efficacious against Cryptosporidium and other apicomplexans that rely on this Type I FAS pathway.

  5. Ubiquitin Drug Discovery and Diagnostics Conference - targeting E3 ligases.

    PubMed

    Johnston, Jennifer A

    2010-10-01

    The Ubiquitin Drug Discovery and Diagnostics Conference, held in Philadelphia, included topics covering the role of E3 ligases in disease. This conference report highlights selected presentations on E3-E2 ligase interactions, the SCF cyclin F ubiquitin ligase complex, and targeting HectH9 and KF-1 E3 ligases. Pharmaceutical research discussed includes E3 programs from Progenra and efforts to modulate the Parkin ligase at Elan Pharmaceuticals.

  6. Antibodies and associates: Partners in targeted drug delivery.

    PubMed

    Kennedy, Patrick J; Oliveira, Carla; Granja, Pedro L; Sarmento, Bruno

    2017-09-01

    Monoclonal antibodies (mAbs) are well established in the clinic due to their specificity and affinity to a diverse array of biochemical targets. More recently, mAbs are being exploited as targeting agents in modern drug delivery systems, aiming to bypass normal host tissue and to accumulate a therapeutic agent to a specific tissue or cell for enhanced pharmacology. At sizes ranging from ~10-100nm, antibody-based bioconjugates have opened up a whole new realm of clinical possibilities with several platforms emerging on the market. Antibody-drug conjugates combine the killing power of cytotoxic agents with mAb specificity and have great potential to treat cancer and beyond. Partnering a mAb with a biologic (protein/peptide, oligonucleotide (ON) or another mAb) is also gaining clinical traction. For example, many bispecific mAbs target and recruit immune effector cells to a tumor, while ON-based therapeutics against intracellular (regulatory) RNAs may be safely delivered into specific cells with mAb support. Finally, nanoparticles (NPs) offer significant drug delivery advantages including controlled release, large and diverse payloads, intracellular delivery and multi-functionality. Coupling mAbs to the surface of NPs can add further targeting capacity, and yet, therapeutic mAbs can also be encapsulated to take advantage of the above NP qualities. Here, we present an updated overview of the different aspects required for the successful development and engineering of antibody bioconjugates in current and emerging drug delivery technologies. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation.

    PubMed

    Meissner, Kamila A; Lunev, Sergey; Wang, Yuan-Ze; Linzke, Marleen; de Assis Batista, Fernando; Wrenger, Carsten; Groves, Matthew R

    2017-01-01

    The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. The current "toolbox" of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Membrane-targeting liquid crystal nanoparticles (LCNPs) for drug delivery

    NASA Astrophysics Data System (ADS)

    Nag, Okhil K.; Naciri, Jawad; Spillmann, Christopher M.; Delehanty, James B.

    2016-03-01

    In addition to maintaining the structural integrity of the cell, the plasma membrane regulates multiple important cellular processes, such as endocytosis and trafficking, apoptotic pathways and drug transport. The modulation or tracking of such cellular processes by means of controlled delivery of drugs or imaging agents via nanoscale delivery systems is very attractive. Nanoparticle-mediated delivery systems that mediate long-term residence (e.g., days) and controlled release of the cargoes in the plasma membrane while simultaneously not interfering with regular cellular physiology would be ideal for this purpose. Our laboratory has developed a plasma membrane-targeted liquid crystal nanoparticle (LCNP) formulation that can be loaded with dyes or drugs which can be slowly released from the particle over time. Here we highlight the utility of these nanopreparations for membrane delivery and imaging.

  9. The opioid receptors as targets for drug abuse medication.

    PubMed

    Noble, Florence; Lenoir, Magalie; Marie, Nicolas

    2015-08-01

    The endogenous opioid system is largely expressed in the brain, and both endogenous opioid peptides and receptors are present in areas associated with reward and motivation. It is well known that this endogenous system plays a key role in many aspects of addictive behaviours. The present review summarizes the modifications of the opioid system induced by chronic treatment with drugs of abuse reported in preclinical and clinical studies, as well as the action of opioid antagonists and agonists on the reinforcing effects of drugs of abuse, with therapeutic perspectives. We have focused on the effects of chronic psychostimulants, alcohol and nicotine exposure. Taken together, the changes in both opioid peptides and opioid receptors in different brain structures following acute or chronic exposure to these drugs of abuse clearly identify the opioid system as a potential target for the development of effective pharmacotherapy for the treatment of addiction and the prevention of relapse.

  10. The opioid receptors as targets for drug abuse medication

    PubMed Central

    Noble, Florence; Lenoir, Magalie; Marie, Nicolas

    2015-01-01

    The endogenous opioid system is largely expressed in the brain, and both endogenous opioid peptides and receptors are present in areas associated with reward and motivation. It is well known that this endogenous system plays a key role in many aspects of addictive behaviours. The present review summarizes the modifications of the opioid system induced by chronic treatment with drugs of abuse reported in preclinical and clinical studies, as well as the action of opioid antagonists and agonists on the reinforcing effects of drugs of abuse, with therapeutic perspectives. We have focused on the effects of chronic psychostimulants, alcohol and nicotine exposure. Taken together, the changes in both opioid peptides and opioid receptors in different brain structures following acute or chronic exposure to these drugs of abuse clearly identify the opioid system as a potential target for the development of effective pharmacotherapy for the treatment of addiction and the prevention of relapse. PMID:25988826

  11. Heart targeted nanoliposomal/nanoparticles drug delivery: An updated review.

    PubMed

    Cheraghi, Mostafa; Negahdari, Babak; Daraee, Hadis; Eatemadi, Ali

    2017-02-01

    Nanoliposomes are type of nano-sized vesicles made of bi-layered phospholipid membranes with an aqueous interior. They have been demonstrated to deliver several materials like low molecular weight drugs, imaging agents, peptides, proteins, and nucleic acids. Nanoliposomes have been demonstrated to slowly release an encapsulated drug, thereby leading to sustained exposure to target region and improved efficacy. This ability of nano-liposomes can be harnessed to deliver therapeutic agents precisely to the infarcted heart. Accordingly, this article will review recent developments in the application of nano liposomes and nanoparticles as drug delivery systems to treat cardiovascular related disorders such as atherosclerosis, restenosis and myocardial infarction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    DTIC Science & Technology

    2014-10-01

    Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT: A. baumannii is a gram -negative bacillus (GNB) known to cause health-care associated...24! 2 W81XWH-11-2-0218 Annual Report October 2014 Introduction& A. baumannii is a gram -negative bacillus (GNB...approach to drug target discovery in multi-drug resistant gram negative bacilli. Future Microbiology. Posters April 2014. K.M. Armbruster

  13. Novel antibacterial compounds and their drug targets - successes and challenges.

    PubMed

    Kaczor, Agnieszka A; Polski, Andrzej; Sobótka-Polska, Karolina; Pachuta-Stec, Anna; Makarska-Bialokoz, Magdalena; Pitucha, Monika

    2016-12-12

    molecular basis of drug resistance, drug targets for novel antibacterial drugs, and new compounds (since year 2010) from different chemical classes with antibacterial activity, focusing on structure-activity relationships.

  14. An immuno-chemo-proteomics method for drug target deconvolution.

    PubMed

    Saxena, Chaitanya; Zhen, Eugene; Higgs, Richard E; Hale, John E

    2008-08-01

    Chemical proteomics is an emerging technique for drug target deconvolution and profiling the toxicity of known drugs. With the use of this technique, the specificity of a small molecule inhibitor toward its potential targets can be characterized and information thus obtained can be used in optimizing lead compounds. Most commonly, small molecules are immobilized on solid supports and used as affinity chromatography resins to bind targets. However, it is difficult to evaluate the effect of immobilization on the affinity of the compounds to their targets. Here, we describe the development and application of a soluble probe where a small molecule was coupled with a peptide epitope which was used to affinity isolate binding proteins from cell lysate. The soluble probe allowed direct verification that the compound after coupling with peptide epitope retained its binding characteristics. The PKC-alpha inhibitor Bisindolylmaleimide-III was coupled with a peptide containing the FLAG epitope. Following incubation with cellular lysates, the compound and associated proteins were affinity isolated using anti-FLAG antibody beads. Using this approach, we identified the known Bisindolylmaleimide-III targets, PKC-alpha, GSK3-beta, CaMKII, adenosine kinase, CDK2, and quinine reductase type 2, as well as previously unidentified targets PKAC-alpha, prohibitin, VDAC and heme binding proteins. This method was directly compared to the solid-phase method (small molecule was immobilized to a solid support) providing an orthogonal strategy to aid in target deconvolution and help to eliminate false positives originating from nonspecific binding of the proteins to the matrix.

  15. Bacterial DNA replication enzymes as targets for antibacterial drug discovery.

    PubMed

    Sanyal, Gautam; Doig, Peter

    2012-04-01

    The bacterial replisome is composed of a large number of enzymes, which work in exquisite coordination to accomplish chromosomal replication. Effective inhibition inside the bacterial cell of any of the 'essential' enzymes of the DNA replication pathway should be detrimental to cell survival. This review covers DNA replication enzymes that have been shown to have a potential for delivering antibacterial compounds or drug candidates including: type II topoisomerases, a clinically validated target family, and DNA ligase, which has yielded inhibitors with in vivo efficacy. A few of the 'replisome' enzymes that are structurally and functionally well characterized and have been subjects of antibacterial discovery efforts are also discussed. Identification of several essential genes in the bacterial replication pathway raised hopes that targeting these gene products would lead to novel antibacterials. However, none of these novel, single gene targets have delivered antibacterial drug candidates into clinical trials. This lack of productivity may be due to the target properties and inhibitor identification approaches employed. For DNA primase, DNA helicase and other replisome targets, with the exception of DNA ligase, the exploitation of structure for lead generation has not been tested to the same extent that it has for DNA gyrase. Utilization of structural information should be considered to augment HTS efforts and initiate fragment-based lead generation. The complex protein-protein interactions involved in regulation of replication may explain why biochemical approaches have been less productive for some replisome targets than more independently functioning targets such as DNA ligase or DNA gyrase. © 2012 Informa UK, Ltd.

  16. Enzyme Tunnels and Gates As Relevant Targets in Drug Design.

    PubMed

    Marques, Sergio M; Daniel, Lukas; Buryska, Tomas; Prokop, Zbynek; Brezovsky, Jan; Damborsky, Jiri

    2017-09-01

    Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules-into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs. © 2016 Wiley Periodicals, Inc.

  17. Rhamnogalacturonan-I Based Microcapsules for Targeted Drug Release

    PubMed Central

    Kusic, Anja; De Gobba, Cristian; Larsen, Flemming H.; Sassene, Philip; Zhou, Qi; van de Weert, Marco; Mullertz, Anette; Jørgensen, Bodil; Ulvskov, Peter

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed, demonstrating that the capsules can be opened by enzymatic degradation. The combined results suggest a potential platform for targeted drug delivery in the terminal gastro-intestinal tract. PMID:27992455

  18. Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

    NASA Astrophysics Data System (ADS)

    Zuccotto, Fabio; Martin, Andrew C. R.; Laskowski, Roman A.; Thornton, Janet M.; Gilbert, Ian H.

    1998-05-01

    Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

  19. Rhamnogalacturonan-I Based Microcapsules for Targeted Drug Release.

    PubMed

    Svagan, Anna J; Kusic, Anja; De Gobba, Cristian; Larsen, Flemming H; Sassene, Philip; Zhou, Qi; van de Weert, Marco; Mullertz, Anette; Jørgensen, Bodil; Ulvskov, Peter

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed, demonstrating that the capsules can be opened by enzymatic degradation. The combined results suggest a potential platform for targeted drug delivery in the terminal gastro-intestinal tract.

  20. Core as a Novel Viral Target for Hepatitis C Drugs

    PubMed Central

    Strosberg, Arthur Donny; Kota, Smitha; Takahashi, Virginia; Snyder, John K.; Mousseau, Guillaume

    2010-01-01

    Hepatitis C virus (HCV) infects over 130 million people worldwide and is a major cause of liver disease. No vaccine is available. Novel specific drugs for HCV are urgently required, since the standard-of-care treatment of pegylated interferon combined with ribavirin is poorly tolerated and cures less than half of the treated patients. Promising, effective direct-acting drugs currently in the clinic have been described for three of the ten potential HCV target proteins: NS3/NS4A protease, NS5B polymerase and NS5A, a regulatory phosphoprotein. We here present core, the viral capsid protein, as another attractive, non-enzymatic target, against which a new class of anti-HCV drugs can be raised. Core plays a major role in the virion’s formation, and interacts with several cellular proteins, some of which are involved in host defense mechanisms against the virus. This most conserved of all HCV proteins requires oligomerization to function as the organizer of viral particle assembly. Using core dimerization as the basis of transfer-of-energy screening assays, peptides and small molecules were identified which not only inhibit core-core interaction, but also block viral production in cell culture. Initial chemical optimization resulted in compounds active in single digit micromolar concentrations. Core inhibitors could be used in combination with other HCV drugs in order to provide novel treatments of Hepatitis C. PMID:21994704

  1. Targeted albumin-based nanoparticles for delivery of amphipathic drugs.

    PubMed

    Xu, Rongzuo; Fisher, Michael; Juliano, R L

    2011-05-18

    We report the preparation and physical and biological characterization of human serum albumin-based micelles of approximately 30 nm diameter for the delivery of amphipathic drugs, represented by doxorubicin. The micelles were surface conjugated with cyclic RGD peptides to guide selective delivery to cells expressing the α(v)β(3) integrin. Multiple poly(ethylene glycol)s (PEGs) with molecular weight of 3400 Da were used to form a hydrophilic outer layer, with the inner core formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity, where each albumin was associated with about 50 doxorubicin molecules. The formed micelles were stable in serum but continuously released doxorubicin when incubated with free thiols at concentrations mimicking the intracellular environment. When incubated with human melanoma cells (M21+) that express the α(v)β(3) integrin, higher uptake and longer retention of doxorubicin was observed with the RGD-targeted micelles than in the case of untargeted control micelles or free doxorubicin. Consequently, the RGD-targeted micelles manifested cytotoxicity at lower doses of drug than control micelles or free drug.

  2. Affinity-based methods in drug-target discovery.

    PubMed

    Rylova, Gabriela; Ozdian, Tomas; Varanasi, Lakshman; Soural, Miroslav; Hlavac, Jan; Holub, Dusan; Dzubak, Petr; Hajduch, Marian

    2015-01-01

    Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the "bench" scientist may be genetic, genomic or proteomic and each has its rightful place in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry (LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of choice for protein identification and quantification. These proteomic tools are critical to maintaining the drug-candidate supply, in the larger context of drug discovery.

  3. Drug target prediction using adverse event report systems: a pharmacogenomic approach.

    PubMed

    Takarabe, Masataka; Kotera, Masaaki; Nishimura, Yosuke; Goto, Susumu; Yamanishi, Yoshihiro

    2012-09-15

    Unexpected drug activities derived from off-targets are usually undesired and harmful; however, they can occasionally be beneficial for different therapeutic indications. There are many uncharacterized drugs whose target proteins (including the primary target and off-targets) remain unknown. The identification of all potential drug targets has become an important issue in drug repositioning to reuse known drugs for new therapeutic indications. We defined pharmacological similarity for all possible drugs using the US Food and Drug Administration's (FDA's) adverse event reporting system (AERS) and developed a new method to predict unknown drug-target interactions on a large scale from the integration of pharmacological similarity of drugs and genomic sequence similarity of target proteins in the framework of a pharmacogenomic approach. The proposed method was applicable to a large number of drugs and it was useful especially for predicting unknown drug-target interactions that could not be expected from drug chemical structures. We made a comprehensive prediction for potential off-targets of 1874 drugs with known targets and potential target profiles of 2519 drugs without known targets, which suggests many potential drug-target interactions that were not predicted by previous chemogenomic or pharmacogenomic approaches. Softwares are available upon request. yamanishi@bioreg.kyushu-u.ac.jp Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/.

  4. Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target.

    PubMed

    Leitsch, David; Müller, Joachim; Müller, Norbert

    2016-12-01

    The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs. TrxR was overexpressed approximately 10-fold in G. lamblia WB C6 cells by placing the trxR gene behind the arginine deiminase (ADI) promoter on a plasmid. Likewise, a mutant TrxR with a defective disulphide reductase catalytic site was strongly expressed in another G. lamblia WB C6 cell line. Susceptibilities to five antigiardial drugs, i.e. metronidazole, furazolidone, nitazoxanide, albendazole and auranofin were determined in both transfectant cell lines and compared to wildtype. Further, the impact of all five drugs on TrxR activity in vivo was measured. Overexpression of TrxR rendered G. lamblia WB C6 more susceptible to metronidazole and furazolidone but not to nitazoxanide, albendazole, and auranofin. Of all five drugs tested, only auranofin had an appreciably negative effect on TrxR activity in vivo, albeit to a much smaller extent than expected. Overexpression of TrxR and mutant TrxR had hardly any impact on growth of G. lamblia WB C6, although the enzyme also exerts a strong NADPH oxidase activity which is a source of oxidative stress. Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs.

  5. Dual responsive PNIPAM-chitosan targeted magnetic nanopolymers for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Yadavalli, Tejabhiram; Ramasamy, Shivaraman; Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal; Chennakesavulu, Ramasamy

    2015-04-01

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation.

  6. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    PubMed

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de.

  7. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development

    PubMed Central

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships. Database URL: http://drumpid.bioapps.biozentrum.uni-wuerzburg.de PMID:27055828

  8. Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery

    NASA Astrophysics Data System (ADS)

    Moyer, Tyson

    The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty

  9. Cyclotriazadisulfonamides: promising new CD4-targeted anti-HIV drugs.

    PubMed

    Vermeire, Kurt; Schols, Dominique

    2005-08-01

    It is imperative to continue efforts to identify novel effective therapies that can assist in containing the spread of HIV. Recently acquired knowledge about the HIV entry process points to new strategies to block viral entry. For most HIV strains, the successful infection of their target cells is mainly dependent on the presence of the CD4 surface molecule, which serves as the primary virus receptor. The attachment of the viral envelope to this cellular CD4 receptor can be considered as an ideal target with multiple windows of opportunity for therapeutic intervention. Therefore, drugs that interfere with the CD4 receptor, and thus inhibit viral entry, may be promising agents for the treatment of AIDS. The CD4-targeted HIV entry inhibitors cyclotriazadisulfonamides represent a novel class of small molecule antiviral agents with a unique mode of action. The lead compound, CADA, specifically interacts with the cellular CD4 receptor and is active against a wide variety of HIV strains at submicromolar levels when evaluated in different cell-types such as T cells, monocytes and dendritic cells. Moreover, a strict correlation has been demonstrated between anti-HIV activity and CD4 interaction of about 20 different CADA analogues. In addition, CADA acted synergistically in combination with all other FDA-approved anti-HIV drugs as well as with compounds that target the main HIV co-receptors. In this article, the characteristics of cyclotriazadisulfonamide compounds are presented and the possible application of CADA as a microbicide is also discussed.

  10. Pharmocoepigenetics: a new approach to predicting individual drug responses and targeting new drugs.

    PubMed

    Baer-Dubowska, Wanda; Majchrzak-Celińska, Aleksandra; Cichocki, Michał

    2011-01-01

    Epigenetics is the study of heritable changes in genes and gene expression that do not involve DNA nucleotide sequences. Epigenetic modifications include DNA methylation, several forms of histone modifications, and microRNA expression. Because of its dynamic nature, epigenetics provides a link between the genome and the environment and fills the gap between DNA and proteins. Advances in epigenetics and epigenomics (the study of epigenetics on a genome-wide basis) have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for variations in drug response. Many genes encoding enzymes, drug transporters, nuclear receptors, and drug targets are under epigenetic control. This review describes the known epigenetic regulation of drug-metabolizing enzymes and other proteins that might affect drug response and compounds that modify the epigenetic status.

  11. Antiepileptic drug effects on mood and behavior: molecular targets.

    PubMed

    Perucca, Piero; Mula, Marco

    2013-03-01

    With almost 100 years of clinical experience, antiepileptic drugs (AEDs) remain the mainstay of epilepsy treatment. They suppress epileptic seizures by acting on a variety of mechanisms and molecular targets involved in the regulation of neuronal excitability. These include inhibitory-GABAergic and excitatory-glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. On the other hand, accruing evidence indicates that these mechanisms and targets are also implicated in the regulation of mood and behavior, which may explain why each AED is associated with specific psychotropic effects. These effects, however, cannot be explained solely on the basis of the known mode of action of each AED, and other mechanisms or targets are likely to be implicated. In this article, we review positive and negative effects of AEDs on mood and behavior, discuss putative underlying mechanisms, and highlight knowledge gaps which should be addressed in future studies.

  12. Anti-Obesity Pharmacotherapy: New Drugs and Emerging Targets

    PubMed Central

    Kim, Gilbert W.; Lin, Jieru E.; Blomain, Erik S.; Waldman, Scott A.

    2014-01-01

    Obesity is a growing pandemic and related health and economic costs are staggering. Pharmacotherapy partnered with lifestyle modifications form the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing anti-obesity therapies, including targets, mechanisms, and developmental status are highlighted. Progress in this field is underscored by Belviq® (lorcaserin) and Qsymia® (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic management weight in obese patients. On the horizon, novel insights in metabolism and energy homeostasis reveal cGMP signaling circuits as emerging targets for anti-obesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches leveraging existing approved drugs that modulate cGMP levels for the management of obesity. PMID:24105257

  13. Acylation in trypanosomatids: an essential process and potential drug target

    PubMed Central

    Goldston, Amanda M.; Sharma, Aabha I.; Paul, Kimberly S.; Engman, David M.

    2014-01-01

    Fatty acylation—the addition of fatty acid moieties such as myristate and palmitate to proteins—is essential for the survival, growth, and infectivity of the trypanosomatids: Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. Myristoylation and palmitoylation are critical for parasite growth, targeting and localization, and the intrinsic function of some proteins. The trypanosomatids possess a single N-myristoyltransferase (NMT) and multiple palmitoyl acyltransferases, and these enzymes and their cellular targets are only now being characterized. Global inhibition of either process leads to cell death in trypanosomatids, and genetic ablation of NMT compromises virulence. Moreover, NMT inhibitors effectively cure T. brucei infection in rodents. Thus, protein acylation represents an attractive target for the development of trypanocidal drugs. PMID:24954795

  14. Non-Spherical Particles for Targeted Drug Delivery

    PubMed Central

    Chen, Jinrong; Clay, Nicholas; Kong, Hyunjoon

    2015-01-01

    Nano- and microparticles loaded with various bioimaging contrast agents or therapeutic molecules have been increasingly used for the diagnosis and treatment of diseases and tissue defects. These particles, often a filled or hollow sphere, can extend the lifetime of encapsulated biomedical modalities in circulation and in target tissue. However, there is a great need to improve the drug loading and targeting efficiency of these particles. Recently, several simulation and in vitro experimental studies reported that particle shape plays a pivotal role in the targeted delivery of molecules. To better understand these findings and subsequently expedite the use of particles in biomedical applications, this review paper summarizes the methods to prepare non-spherical nano- and micro-scaled particles. In addition, this review covers studies reporting the effects of particle shape on the loading, delivery and release of encapsulated bioactive cargos. Finally, it discusses future directions to further improve the properties of non-spherical particles. PMID:25838583

  15. Heme Aggregation inhibitors: antimalarial drugs targeting an essential biomineralization process.

    PubMed

    Ziegler, J; Linck, R; Wright, D W

    2001-02-01

    Malaria, resulting from the parasites of the genus Plasmodium, places an untold burden on the global population. As recently as 40 years ago, only 10% of the world's population was at risk from malaria. Today, over 40% of the world's population is at risk. Due to increased parasite resistance to traditional drugs and vector resistance to insecticides, malaria is once again resurgent. An emergent theme from current strategies for the development of new antimalarials is that metal homeostasis within the parasite represents an important drug target. During the intra-erythrocytic phase of its life cycle, the malaria parasite can degrade up to 75% of an infected cell's hemoglobin. While hemoglobin proteolysis yields requisite amino acids, it also releases toxic free heme (Fe(III)PPIX). To balance the metabolic requirements for amino acids against the toxic effects of heme, malaria parasites have evolved a detoxification mechanism which involves the formation of a crystalline heme aggregate known as hemozoin. An overview of the biochemistry of the critical detoxification process will place it in the appropriate context with regards to drug targeting and design. Quinoline-ring antimalarial drugs are effective against the intraerythrocytic stages of pigment-producing parasites. Recent work on the mechanism of these compounds suggests that they prevent the formation of hemozoin. Evidence for such a mechanism is reviewed, especially in the context of the newly reported crystal structure of hemozoin. Additionally, novel drugs, such as the hydroxyxanthones, which have many of the characteristics of the quinolines are currently being investigated. Recent work has also highlighted two classes of inorganic complexes that have interesting antimalarial activity: (1) metal-N(4)O(2) Schiff base complexes and (2) porphyrins. The mechanism of action for these complexes is discussed. The use of these complexes as probes for the elucidation of structure-activity relationships in heme

  16. Drug Affinity Responsive Target Stability (DARTS) for Small Molecule Target Identification

    PubMed Central

    Hwang, Heejun; Schiestl, Robert; McBride, William; Loo, Joseph A.; Huang, Jing

    2015-01-01

    Drug Affinity Responsive Target Stability (DARTS) is a relatively quick and straightforward approach to identify potential protein targets for small molecules. It relies on the protection against proteolysis conferred on the target protein by interaction with a small molecule. The greatest advantage of this method is being able to use the native small molecule without having to immobilize or modify it (e.g. by incorporation of biotin, fluorescent, radioisotope, or photo-affinity labels). Here we describe in detail the protocol for performing unbiased DARTS with complex protein lysate to identify potential binding targets of small molecules and for using DARTS-Western blotting to test, screen, or validate potential small molecule targets. Although the ideas have mainly been developed from studying molecules in areas of biology that are currently of interest to us and our collaborators, the general principles should be applicable to the analysis of all molecules in nature. PMID:25618353

  17. Internalized compartments encapsulated nanogels for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Yu, Jicheng; Zhang, Yuqi; Sun, Wujin; Wang, Chao; Ranson, Davis; Ye, Yanqi; Weng, Yuyan; Gu, Zhen

    2016-04-01

    Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The

  18. Cardiac calmodulin kinase: a potential target for drug design.

    PubMed

    Bányász, T; Szentandrássy, N; Tóth, A; Nánási, P P; Magyar, J; Chen-Izu, Y

    2011-01-01

    Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as ßblockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and

  19. Cardiac Calmodulin Kinase: A Potential Target for Drug Design

    PubMed Central

    Bányász, T.; Szentandrássy, N.; Tóth, A.; Nánási, P.P.; Magyar, J.; Chen-Izu, Y.

    2014-01-01

    Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as β-blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and

  20. Iron Acquisition Pathways as Targets for Antitubercular Drugs.

    PubMed

    Meneghetti, Fiorella; Villa, Stefania; Gelain, Arianna; Barlocco, Daniela; Chiarelli, Laurent Roberto; Pasca, Maria Rosalia; Costantino, Luca

    2016-01-01

    Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4'-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.

  1. Application of RNAi to Genomic Drug Target Validation in Schistosomes

    PubMed Central

    Guidi, Alessandra; Mansour, Nuha R.; Paveley, Ross A.; Carruthers, Ian M.; Besnard, Jérémy; Hopkins, Andrew L.; Gilbert, Ian H.; Bickle, Quentin D.

    2015-01-01

    Concerns over the possibility of resistance developing to praziquantel (PZQ), has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi) in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets. Initially a list of 24 target candidates was compiled based on the identification of putative essential genes in schistosomes orthologous of C. elegans essential genes. Knockdown of Calmodulin (Smp_026560.2) (Sm-Calm), that topped this list, produced a phenotype characterised by waves of contraction in adult worms but no phenotype in schistosomula. Knockdown of the atypical Protein Kinase C (Smp_096310) (Sm-aPKC) resulted in loss of viability in both schistosomula and adults and led us to focus our attention on other kinase genes that were identified in the above list and through whole organism screening of known kinase inhibitor sets followed by chemogenomic evaluation. RNAi knockdown of these kinase genes failed to affect adult worm viability but, like Sm-aPKC, knockdown of Polo-like kinase 1, Sm-PLK1 (Smp_009600) and p38-MAPK, Sm-MAPK p38 (Smp_133020) resulted in an increased mortality of schistosomula after 2-3 weeks, an effect more marked in the presence of human red blood cells (hRBC). For Sm-PLK-1 the same effects were seen with the specific inhibitor, BI2536, which also affected viable egg production in adult worms. For Sm-PLK-1 and Sm-aPKC the in vitro effects were reflected in lower recoveries in vivo. We conclude that the use of RNAi combined with culture with hRBC is a reliable method for evaluating genes important for larval development. However, in view of the slow manifestation of the effects of Sm-aPKC knockdown in adults and the lack of effects of Sm-PLK-1 and Sm-MAPK p38 on adult viability, these

  2. ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions.

    PubMed

    Marquez, Béatrice; Van Bambeke, Françoise

    2011-05-01

    Nine proteins of the ABC superfamily (P-glycoprotein, 7 MRPs and BCRP) are involved in multidrug transport. Being localised at the surface of endothelial or epithelial cells, they expel drugs back to the external medium (if located at the apical side [P-glycoprotein, BCRP, MRP2, MRP4 in the kidney]) or to the blood (if located at the basolateral side [MRP1, MRP3, MRP4, MRP5]), modulating thereby their absorption, distribution, and elimination. In the CNS, most transporters are oriented to expel drugs to the blood. Transporters also cooperate with Phase I/Phase II metabolism enzymes by eliminating drug metabolites. Their major features are (i) their capacity to recognize drugs belonging to unrelated pharmacological classes, and (ii) their redundancy, a single molecule being possibly substrate for different transporters. This ensures an efficient protection of the body against invasion by xenobiotics. Competition for transport is now characterized as a mechanism of interaction between co-administered drugs, one molecule limiting the transport of the other, potentially affecting bioavailability, distribution, and/or elimination. Again, this mechanism reinforces drug interactions mediated by cytochrome P450 inhibition, as many substrates of P-glycoprotein and CYP3A4 are common. Induction of the expression of genes coding for MDR transporters is another mechanism of drug interaction, which could affect all drug substrates of the up-regulated transporter. Overexpression of MDR transporters confers resistance to anticancer agents and other therapies. All together, these data justify why studying drug active transport should be part of the evaluation of new drugs, as recently recommended by the FDA.

  3. Physics considerations in targeted anticancer drug delivery by magnetoelectric nanoparticles

    NASA Astrophysics Data System (ADS)

    Stimphil, Emmanuel; Nagesetti, Abhignyan; Guduru, Rakesh; Stewart, Tiffanie; Rodzinski, Alexandra; Liang, Ping; Khizroev, Sakhrat

    2017-06-01

    In regard to cancer therapy, magnetoelectric nanoparticles (MENs) have proven to be in a class of its own when compared to any other nanoparticle type. Like conventional magnetic nanoparticles, they can be used for externally controlled drug delivery via application of a magnetic field gradient and image-guided delivery. However, unlike conventional nanoparticles, due to the presence of a non-zero magnetoelectric effect, MENs provide a unique mix of important properties to address key challenges in modern cancer therapy: (i) a targeting mechanism driven by a physical force rather than antibody matching, (ii) a high-specificity delivery to enhance the cellular uptake of therapeutic drugs across the cancer cell membranes only, while sparing normal cells, (iii) an externally controlled mechanism to release drugs on demand, and (iv) a capability for image guided precision medicine. These properties separate MEN-based targeted delivery from traditional biotechnology approaches and lay a foundation for the complementary approach of technobiology. The biotechnology approach stems from the underlying biology and exploits bioinformatics to find the right therapy. In contrast, the technobiology approach is geared towards using the physics of molecular-level interactions between cells and nanoparticles to treat cancer at the most fundamental level and thus can be extended to all the cancers. This paper gives an overview of the current state of the art and presents an ab initio model to describe the underlying mechanisms of cancer treatment with MENs from the perspective of basic physics.

  4. Strategies for skeletal muscle targeting in drug discovery.

    PubMed

    Ebner, David C; Bialek, Peter; El-Kattan, Ayman F; Ambler, Catherine M; Tu, Meihua

    2015-01-01

    The targeting of drugs to skeletal muscle is an emerging area of research. Driven by the need for new therapies to treat a range of muscle-associated diseases, these strategies aim to provide improved drug exposure at the site of action in skeletal muscle with reduced concentration in other tissues where unwanted side effects could occur. By interacting with muscle-specific cell surface recognition elements, both tissue localization and selective uptake into skeletal muscle cells can be achieved. The design of molecules that are substrates for muscle uptake transporters can provide concentration in m uscle tissue. For example, drug conjugates with carnitine can provide improved muscle uptake via OCTN2 transport. Binding to muscle surface recognition elements followed by endocytosis can allow even large molecules such as antibodies to enter muscle cells. Monoclonal antibody 3E10 demonstrated selective uptake into skeletal muscle in vivo. Hybrid adeno-associated viral vectors have recently shown promise for high skeletal muscle selectivity in gene transfer applications. Delivery technology methods, including electroporation of DNA plasmids, have also been investigated for selective muscle uptake. This review discusses challenges and opportunities for skeletal muscle targeting, highlighting specific examples and areas in need of additional research.

  5. Ultrasound-sensitive nanoparticle aggregates for targeted drug delivery.

    PubMed

    Papa, Anne-Laure; Korin, Netanel; Kanapathipillai, Mathumai; Mammoto, Akiko; Mammoto, Tadanori; Jiang, Amanda; Mannix, Robert; Uzun, Oktay; Johnson, Christopher; Bhatta, Deen; Cuneo, Garry; Ingber, Donald E

    2017-09-01

    Here we describe injectable, ultrasound (US)-responsive, nanoparticle aggregates (NPAs) that disintegrate into slow-release, nanoscale, drug delivery systems, which can be targeted to selective sites by applying low-energy US locally. We show that, unlike microbubble based drug carriers which may suffer from stability problems, the properties of mechanical activated NPAs, composed of polymer nanoparticles, can be tuned by properly adjusting the polymer molecular weight, the size of the nanoparticle precursors as well as the percentage of excipient utilized to hold the NPA together. We then apply this concept to practice by fabricating NPAs composed of nanoparticles loaded with Doxorubicin (Dox) and tested their ability to treat tumors via ultrasound activation. Mouse studies demonstrated significantly increased efficiency of tumor targeting of the US-activated NPAs compared to PLGA nanoparticle controls (with or without US applied) or intact NPAs. Importantly, when the Dox-loaded NPAs were injected and exposed to US energy locally, this increased ability to concentrate nanoparticles at the tumor site resulted in a significantly greater reduction in tumor volume compared to tumors treated with a 20-fold higher dose of the free drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Validating Aurora B as an anti-cancer drug target.

    PubMed

    Girdler, Fiona; Gascoigne, Karen E; Eyers, Patrick A; Hartmuth, Sonya; Crafter, Claire; Foote, Kevin M; Keen, Nicholas J; Taylor, Stephen S

    2006-09-01

    The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.

  7. Targeted Tumor Therapy with "Magnetic Drug Targeting": Therapeutic Efficacy of Ferrofluid Bound Mitoxantrone

    NASA Astrophysics Data System (ADS)

    Alexiou, Ch.; Schmid, R.; Jurgons, R.; Bergemann, Ch.; Arnold, W.; Parak, F.G.

    The difference between success or failure of chemotherapy depends not only on the drug itself but also on how it is delivered to its target. Biocompatible ferrofluids (FF) are paramagnetic nanoparticles, that may be used as a delivery system for anticancer agents in locoregional tumor therapy, called "magnetic drug targeting". Bound to medical drugs, such magnetic nanoparticles can be enriched in a desired body compartment (tumor) using an external magnetic field, which is focused on the area of the tumor. Through this form of target directed drug application, one attempts to concentrate a pharmacological agent at its site of action in order to minimize unwanted side effects in the organism and to increase its locoregional effectiveness. Tumor bearing rabbits (VX2 squamous cell carcinoma) in the area of the hind limb, were treated by a single intra-arterial injection (A. femoralis) of mitoxantrone bound ferrofluids (FF-MTX), while focusing an external magnetic field (1.7 Tesla) onto the tumor for 60 minutes. Complete tumor remissions could be achieved in these animals in a dose related manner (20% and 50% of the systemic dose of mitoxantrone), without any negative side effects, like e.g. leucocytopenia, alopecia or gastrointestinal disorders. The strong and specific therapeutic efficacy in tumor treatment with mitoxantrone bound ferrofluids may indicate that this system could be used as a delivery system for anticancer agents, like radionuclids, cancer-specific antibodies, anti-angiogenetic factors, genes etc.

  8. CRIMALDDI: platform technologies and novel anti-malarial drug targets.

    PubMed

    Vial, Henri; Taramelli, Donatella; Boulton, Ian C; Ward, Steve A; Doerig, Christian; Chibale, Kelly

    2013-11-05

    The Coordination, Rationalization, and Integration of antiMALarial drug Discovery & Development Initiatives (CRIMALDDI) Consortium, funded by the EU Framework Seven Programme, has attempted, through a series of interactive and facilitated workshops, to develop priorities for research to expedite the discovery of new anti-malarials. This paper outlines the recommendations for the development of enabling technologies and the identification of novel targets.Screening systems must be robust, validated, reproducible, and represent human malaria. They also need to be cost-effective. While such systems exist to screen for activity against blood stage Plasmodium falciparum, they are lacking for other Plasmodium spp. and other stages of the parasite's life cycle. Priority needs to be given to developing high-throughput screens that can identify activity against the liver and sexual stages. This in turn requires other enabling technologies to be developed to allow the study of these stages and to allow for the culture of liver cells and the parasite at all stages of its life cycle.As these enabling technologies become available, they will allow novel drug targets to be studied. Currently anti-malarials are mostly targeting the asexual blood stage of the parasite's life cycle. There are many other attractive targets that need to be investigated. The liver stages and the sexual stages will become more important as malaria control moves towards malaria elimination. Sexual development is a process offering multiple targets, even though the mechanisms of differentiation are still not fully understood. However, designing a drug whose effect is not curative but would be used in asymptomatic patients is difficult given current safety thresholds. Compounds active against the liver schizont would have a prophylactic effect and Plasmodium vivax elimination requires effectors against the dormant liver hypnozoites. It may be that drugs to be used in elimination campaigns will also need

  9. DNA helicases as targets for anti-cancer drugs.

    PubMed

    Sharma, Sudha; Doherty, Kevin M; Brosh, Robert M

    2005-05-01

    DNA helicases have essential roles in nucleic acid metabolism by facilitating cellular processes including replication, recombination, DNA repair, and transcription. The vital roles of helicases in these pathways are reflected by their emerging importance in the maintenance of genomic stability. Recently, a number of human diseases with cancer predisposition have been shown to be genetically linked to a specific helicase defect. This has led researchers to further investigate the roles of helicases in cancer biology, and to study the efficacy of targeting human DNA helicases for anti-cancer drug treatment. Helicase-specific inhibition in malignant cells may compromise the high proliferation rates of cancerous tissues. The role of RecQ helicases in response to replicational stress suggests a molecular target for selectively eliminating malignant tumor cells by a cancer chemotherapeutic agent. Alternate DNA secondary structures such as G-quadruplexes that may form in regulatory regions of oncogenes or G-rich telomere sequences are potential targets for cancer therapy since these sequence-specific structures are proposed to affect gene expression and telomerase activation, respectively. Small molecule inhibitors of G-quadruplex helicases may be used to regulate cell cycle progression by modulating promotor activation or disrupting telomere maintenance, important processes of cellular transformation. The design of small molecules which deter helicase function at telomeres may provide a molecular target since telomerase activity is necessary for the proliferation of numerous immortal cells. Although evidence suggests that helicases are specifically inhibited by certain DNA binding compounds, another area of promise in anti-cancer therapy is siRNA technology. Specific knockdown of helicase expression can be utilized as a means to sensitize oncogenic proliferating cell lines. This review will address these topics in detail and summarize the current avenues of research in

  10. Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

    PubMed Central

    Sehgal, Sheikh Arslan; Hassan, Mubashir; Rashid, Sajid

    2014-01-01

    Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18). Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine. PMID:24899801

  11. Pleiotropic effects of statins: new therapeutic targets in drug design.

    PubMed

    Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

    2016-07-01

    The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

  12. Drug targeting to myofibroblasts: Implications for fibrosis and cancer.

    PubMed

    Yazdani, Saleh; Bansal, Ruchi; Prakash, Jai

    2017-07-16

    Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of myofibroblasts in tumor progression, invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor progression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will then discuss the state-of-the art drug targeting technologies to myofibroblasts in context of the above-mentioned organs and tumor microenvironment. The overall objective of this review is therefore to advance our understanding in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for designing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

    PubMed Central

    Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C.; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon B.; Altieri, Dario C.; Flaherty, Keith T.

    2016-01-01

    Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. PMID:27043285

  14. Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery

    NASA Astrophysics Data System (ADS)

    Chu, Hsiao Mei Annie

    2011-12-01

    Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and

  15. Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.

    PubMed

    Shakespeare, William C; Metcalf, Chester A; Wang, Yihan; Sundaramoorthi, Raji; Keenan, Terence; Weigele, Manfred; Bohacek, Regine S; Dalgarno, David C; Sawyer, Tomi K

    2003-09-01

    Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone-targeted

  16. New drugs in psychiatry: focus on new pharmacological targets

    PubMed Central

    Caraci, Filippo; Leggio, Gian Marco; Salomone, Salvatore; Drago, Filippo

    2017-01-01

    The approval of psychotropic drugs with novel mechanisms of action has been rare in recent years. To address this issue, further analysis of the pathophysiology of neuropsychiatric disorders is essential for identifying new pharmacological targets for psychotropic medications. In this report, we detail drug candidates being examined as treatments for psychiatric disorders. Particular emphasis is placed on agents with novel mechanisms of action that are being tested as therapies for depression, schizophrenia, or Alzheimer’s disease. All of the compounds considered were recently approved for human use or are in advanced clinical trials. Drugs included here are new antipsychotic medications endowed with a preferential affinity at dopamine D3 receptor (cariprazine) or at glutamatergic or cannabinoid receptors, as well as vortioxetine, a drug approved for managing the cognitive deficits associated with major depression. New mechanistic approaches for the treatment of depression include intravenous ketamine or esketamine or intranasal esketamine. As for Alzheimer’s disease, the possible value of passive immunotherapy with agents such as aducanumab is considered to be a potential disease-modifying approach that could slow or halt the progressive decline associated with this devastating disorder. PMID:28408985

  17. Nanostructured lipid carriers (NLCs) for drug delivery and targeting.

    PubMed

    Fang, Chia-Lang; Al-Suwayeh, Saleh A; Fang, Jia-You

    2013-01-01

    Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated.

  18. Magnetically responsive microparticles for targeted drug and radionuclide delivery.

    SciTech Connect

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-02-16

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 {micro}m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 {micro}m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 {micro}m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  19. Protein kinases as targets for antiparasitic chemotherapy drugs.

    PubMed

    Canduri, Fernanda; Perez, Patrícia Cardoso; Caceres, Rafael A; de Azevedo, Walter F

    2007-03-01

    Parasitic protozoa infecting humans have a great impact on public health, especially in the developing countries. In many instances, the parasites have developed resistance against available chemotherapeutic agents, making the search for alternative drugs a priority. In line with the current interest in Protein Kinase (PK) inhibitors as potential drugs against a variety of diseases, the possibility that PKs may represent targets for novel anti-parasitic agents is being explored. Research into parasite PKs has benefited greatly from genome and EST sequencing projects, with the genomes from a few species fully sequenced (notably that from the malaria parasite Plasmodium falciparum) and several more under way, the structural features that are important to design specific inhibitors against these PKs will be reviewed in the present work.

  20. Drug targets for rational design against emerging coronaviruses.

    PubMed

    Zhao, Qi; Weber, Erin; Yang, Haitao

    2013-04-01

    The recent, fatal outbreak of the novel coronavirus strain in the Middle East highlights the real threat posed by this unique virus family. Neither pharmaceutical cures nor preventive vaccines are clinically available to fight against coronavirus associated syndromes, not to mention a lack of symptom soothing drugs. Development of treatment options is complicated by the unpredictable, recurring instances of cross-species viral transmission. The vastly distributing virus reservoir and the rapid rate of host-species exchange of coronavirus demands wide spectrum potency in an ideal therapeutic. Through summarizing the available information and progress in coronavirus research, this review provides a systematic assessment of the potential wide-spectrum features on the most popular drug targets including viral proteases, spike protein, RNA polymerases and editing enzymes as well as host-virus interaction pathways associated with coronaviruses.

  1. Candidate Drug Targets for Prevention or Modification of Epilepsy

    PubMed Central

    Varvel, Nicholas H.; Jiang, Jianxiong; Dingledine, Raymond

    2015-01-01

    Epilepsy is a prevalent neurological disorder afflicting nearly 50 million people worldwide. The disorder is characterized clinically by recurrent spontaneous seizures attributed to abnormal synchrony of brain neurons. Despite advances in the treatment of epilepsy, nearly one-third of patients are resistant to current therapies, and the underlying mechanisms whereby a healthy brain becomes epileptic remain unresolved. Therefore, researchers have a major impetus to identify and exploit new drug targets. Here we distinguish between epileptic effectors, or proteins that set the seizure threshold, and epileptogenic mediators, which control the expression or functional state of the effector proteins. Under this framework, we then discuss attempts to regulate the mediators to control epilepsy. Further insights into the complex processes that render the brain susceptible to seizures and the identification of novel mediators of these processes will lead the way to the development of drugs to modify disease outcome and, potentially, to prevent epileptogenesis. PMID:25196047

  2. Cognitive 'Omics': Pattern-Based Validation of Potential Drug Targets.

    PubMed

    Gyertyán, István

    2017-02-01

    Despite the abundance of cognitive enhancer mechanisms identified in basic research, drugs approved for cognitive disorders are scarce and of limited efficacy. Although the so-called 'gold-standard' animal assays are well suited to the study of fundamental learning processes, they fail to predict clinical efficacy against complex and robust cognitive defects. Preclinical validation of potential drug targets requires new approaches with higher translational value. Here I propose a rodent cognitive test system that encompasses several learning paradigms each modeling a certain human cognitive domain. Cognitive deficits are brought about by several impairing methods and a particular mechanism of action is tested on each defective cognitive function. The outcome is a cognitive efficacy pattern that should then be matched to the cognitive deficit patterns of the clinical disorders. The best fit will highlight the clinical indication with the greatest chance for success.

  3. Genome-Scale Screening of Drug-Target Associations Relevant to Ki Using a Chemogenomics Approach

    PubMed Central

    Cao, Dong-Sheng; Liang, Yi-Zeng; Deng, Zhe; Hu, Qian-Nan; He, Min; Xu, Qing-Song; Zhou, Guang-Hua; Zhang, Liu-Xia; Deng, Zi-xin; Liu, Shao

    2013-01-01

    The identification of interactions between drugs and target proteins plays a key role in genomic drug discovery. In the present study, the quantitative binding affinities of drug-target pairs are differentiated as a measurement to define whether a drug interacts with a protein or not, and then a chemogenomics framework using an unbiased set of general integrated features and random forest (RF) is employed to construct a predictive model which can accurately classify drug-target pairs. The predictability of the model is further investigated and validated by several independent validation sets. The built model is used to predict drug-target associations, some of which were confirmed by comparing experimental data from public biological resources. A drug-target interaction network with high confidence drug-target pairs was also reconstructed. This network provides further insight for the action of drugs and targets. Finally, a web-based server called PreDPI-Ki was developed to predict drug-target interactions for drug discovery. In addition to providing a high-confidence list of drug-target associations for subsequent experimental investigation guidance, these results also contribute to the understanding of drug-target interactions. We can also see that quantitative information of drug-target associations could greatly promote the development of more accurate models. The PreDPI-Ki server is freely available via: http://sdd.whu.edu.cn/dpiki. PMID:23577055

  4. Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

    PubMed Central

    Ndieyira, Joseph W.; Watari, Moyu; McKendry, Rachel A.

    2013-01-01

    The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity1-5. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures1,6,7. We developed a new model1 which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of

  5. Nanomechanics of drug-target interactions and antibacterial resistance detection.

    PubMed

    Ndieyira, Joseph W; Watari, Moyu; McKendry, Rachel A

    2013-10-25

    The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures. We developed a new model(1) which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful

  6. The electrospray and its application to targeted drug inhalation.

    PubMed

    Gomez, Alessandro

    2002-12-01

    This review explains the fundamentals of electrostatic spray (electrospray) atomization, with emphasis on operation in the so called cone-jet mode, which produces droplets with a very narrow size distribution. Since the control of droplet size is key to maximizing distal lung deposition, the electrospray should be well-suited to targeted drug inhalation. Electrospray droplets are a few micrometers in diameter, but they originate from a much larger nozzle, which allows nebulization of suspensions without clogging. Also discussed are: the physical principles of the break-up of the liquid ligament; droplet dispersion by Coulombic forces; and the most important scaling law linking the droplet size to liquid flow rate and liquid physical properties. The effects of the most critical of those properties may result in some restrictions on drug formulation. Droplets produced by electrospray are electrically charged, so to prevent electrostatic image forces from causing upper respiratory tract deposition. The charge is neutralized by generating a corona discharge of opposite polarity. Briefly discussed are the main differences between the laboratory systems (with which the electrospray has been quantitatively characterized during research in the past 10 years) and commercial electrospray inhalers under development at BattellePharma. Some remarkable miniaturization has incorporated liquid pump, power supply, breath activation, and dose counter into a palm-size portable device. The maximum flow rates dispersed from these devices are in the range of 8-16 microL/s, which makes them suitable for practical drug inhalation therapy. Fabrication is economically competitive with inexpensive nebulizers. Dramatic improvements in respirable dose efficiency (up to 78% by comparison with commercial metered-dose inhalers and dry powder inhalers) should ensure the commercialization of this promising technology for targeted drug inhalation.

  7. Drug target prediction using adverse event report systems: a pharmacogenomic approach

    PubMed Central

    Takarabe, Masataka; Kotera, Masaaki; Nishimura, Yosuke; Goto, Susumu; Yamanishi, Yoshihiro

    2012-01-01

    Motivation: Unexpected drug activities derived from off-targets are usually undesired and harmful; however, they can occasionally be beneficial for different therapeutic indications. There are many uncharacterized drugs whose target proteins (including the primary target and off-targets) remain unknown. The identification of all potential drug targets has become an important issue in drug repositioning to reuse known drugs for new therapeutic indications. Results: We defined pharmacological similarity for all possible drugs using the US Food and Drug Administration's (FDA's) adverse event reporting system (AERS) and developed a new method to predict unknown drug–target interactions on a large scale from the integration of pharmacological similarity of drugs and genomic sequence similarity of target proteins in the framework of a pharmacogenomic approach. The proposed method was applicable to a large number of drugs and it was useful especially for predicting unknown drug–target interactions that could not be expected from drug chemical structures. We made a comprehensive prediction for potential off-targets of 1874 drugs with known targets and potential target profiles of 2519 drugs without known targets, which suggests many potential drug–target interactions that were not predicted by previous chemogenomic or pharmacogenomic approaches. Availability: Softwares are available upon request. Contact: yamanishi@bioreg.kyushu-u.ac.jp Supplementary Information: Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/. PMID:22962489

  8. Rho, ROCK and actomyosin contractility in metastasis as drug targets

    PubMed Central

    Bruce, Fanshawe; Sanz-Moreno, Victoria

    2016-01-01

    Metastasis is the spread of cancer cells around the body and the cause of the majority of cancer deaths. Metastasis is a very complex process in which cancer cells need to dramatically modify their cytoskeleton and cope with different environments to successfully colonize a secondary organ. In this review, we discuss recent findings pointing at Rho-ROCK or actomyosin force (or both) as major drivers of many of the steps required for metastatic success. We propose that these are important drug targets that need to be considered in the clinic to palliate metastatic disease. PMID:27158478

  9. Mining nematode genome data for novel drug targets.

    PubMed

    Foster, Jeremy M; Zhang, Yinhua; Kumar, Sanjay; Carlow, Clotilde K S

    2005-03-01

    Expressed sequence tag projects have currently produced over 400 000 partial gene sequences from more than 30 nematode species and the full genomic sequences of selected nematodes are being determined. In addition, functional analyses in the model nematode Caenorhabditis elegans have addressed the role of almost all genes predicted by the genome sequence. This recent explosion in the amount of available nematode DNA sequences, coupled with new gene function data, provides an unprecedented opportunity to identify pre-validated drug targets through efficient mining of nematode genomic databases. This article describes the various information sources available and strategies that can expedite this process.

  10. TRPV1: A Target for Rational Drug Design

    PubMed Central

    Carnevale, Vincenzo; Rohacs, Tibor

    2016-01-01

    Transient Receptor Potential Vanilloid 1 (TRPV1) is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX). Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures. PMID:27563913

  11. Pharmacytes: an ideal vehicle for targeted drug delivery.

    PubMed

    Freitas, Robert A

    2006-01-01

    An ideal nanotechnology-based drug delivery system is a pharmacyte--a self-powered, computer-controlled medical nanorobot system capable of digitally precise transport, timing, and targeted delivery of pharmaceutical agents to specific cellular and intracellular destinations within the human body. Pharmacytes may be constructed using future molecular manufacturing technologies such as diamond mechanosynthesis which are currently being investigated theoretically using quantum ab initio and density-functional computational methods. Pharmacytes will have many applications in nanomedicine such as initiation of apoptosis in cancer cells and direct control of cell signaling processes.

  12. Orphan Nuclear Receptors as Targets for Drug Development

    PubMed Central

    Mukherjee, Subhajit

    2012-01-01

    Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994

  13. Modular Nanotransporters for Targeted Intracellular Delivery of Drugs: Folate Receptors as Potential Targets

    PubMed Central

    Slastnikova, Tatiana A.; Rosenkranz, Andrey A.; Zalutsky, Michael R.; Sobolev, Alexander S.

    2015-01-01

    The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells. PMID:25312738

  14. Drug targets in the cytokine universe for autoimmune disease.

    PubMed

    Liu, Xuebin; Fang, Lei; Guo, Taylor B; Mei, Hongkang; Zhang, Jingwu Z

    2013-03-01

    In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Inhibition of bacterial ribosome assembly: a suitable drug target?

    PubMed

    Maguire, Bruce A

    2009-03-01

    The assembly of bacterial ribosomes is viewed with increasing interest as a potential target for new antibiotics. The in vivo synthesis and assembly of ribosomes are briefly reviewed here, highlighting the many ways in which assembly can be perturbed. The process is compared with the model in vitro process from which much of our knowledge is derived. The coordinate synthesis of the ribosomal components is essential for their ordered and efficient assembly; antibiotics interfere with this coordination and therefore affect assembly. It has also been claimed that the binding of antibiotics to nascent ribosomes prevents their assembly. These two contrasting models of antibiotic action are compared and evaluated. Finally, the suitability and tractability of assembly as a drug target are assessed.

  16. Novel drugs targeting Toll-like receptors for antiviral therapy

    PubMed Central

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge CG

    2014-01-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved ‘pathogen-associated molecular patterns’ of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release ‘danger-associated molecular patterns’ that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy. PMID:25620999

  17. Toxoplasma histone acetylation remodelers as novel drug targets

    PubMed Central

    Vanagas, Laura; Jeffers, Victoria; Bogado, Silvina S; Dalmasso, Maria C; Sullivan, William J; Angel, Sergio O

    2013-01-01

    Toxoplasma gondii is a leading cause of neurological birth defects and a serious opportunistic pathogen. The authors and others have found that Toxoplasma uses a unique nucleosome composition supporting a fine gene regulation together with other factors. Post-translational modifications in histones facilitate the establishment of a global chromatin environment and orchestrate DNA-related biological processes. Histone acetylation is one of the most prominent post-translational modifications influencing gene expression. Histone acetyltransferases and histone deacetylases have been intensively studied as potential drug targets. In particular, histone deacetylase inhibitors have activity against apicomplexan parasites, underscoring their potential as a new class of antiparasitic compounds. In this review, we summarize what is known about Toxoplasma histone acetyltransferases and histone deacetylases, and discuss the inhibitors studied to date. Finally, the authors discuss the distinct possibility that the unique nucleosome composition of Toxoplasma, which harbors a nonconserved H2Bv variant histone, might be targeted in novel therapeutics directed against this parasite. PMID:23199404

  18. A kidney-selective biopolymer for targeted drug delivery.

    PubMed

    Bidwell, Gene L; Mahdi, Fakhri; Shao, Qingmei; Logue, Omar C; Waller, Jamarius P; Reese, Caleb; Chade, Alejandro R

    2017-01-01

    Improving drug delivery to the kidney using renal-targeted therapeutics is a promising but underdeveloped area. We aimed to develop a kidney-targeting construct for renal-specific drug delivery. Elastin-like polypeptides (ELPs) are nonimmunogenic protein-based carriers that can stabilize attached small-molecule and peptide therapeutics. We modified ELP at its NH2-terminus with a cyclic, seven-amino acid kidney-targeting peptide (KTP) and at its COOH-terminus with a cysteine residue for tracer conjugation. Comparative in vivo pharmacokinetics and biodistribution in rat and swine models and in vitro cell binding studies using human renal cells were performed. KTP-ELP had a longer plasma half-life than ELP in both animal models and was similarly accumulated in kidneys at levels fivefold higher than untargeted ELP, showing renal levels 15- to over 150-fold higher than in other major organs. Renal fluorescence histology demonstrated high accumulation of KTP-ELP in proximal tubules and vascular endothelium. Furthermore, a 14-day infusion of a high dose of ELP or KTP-ELP did not affect body weight, glomerular filtration rate, or albuminuria, or induce renal tissue damage compared with saline-treated controls. In vitro experiments showed higher binding of KTP-ELP to human podocytes, proximal tubule epithelial, and glomerular microvascular endothelial cells than untargeted ELP. These results show the high renal selectivity of KTP-ELP, support the notion that the construct is not species specific, and demonstrate that it does not induce acute renal toxicity. The plasticity of ELP for attachment of any class of therapeutics unlocks the possibility of applying ELP technology for targeted treatment of renal disease in future studies. Copyright © 2017 the American Physiological Society.

  19. RGD based peptide amphiphiles as drug carriers for cancer targeting

    NASA Astrophysics Data System (ADS)

    Saraf, Poonam S.

    Specific interactions of ligands with receptors is one of the approaches for active targeting of anticancer drugs to cancer cells. Over expression of integrin receptors is a physiological manifestation in several cancers and is associated with cancer progression and metastasis, which makes it an attractive target for cancer chemotherapy. The peptide sequence for this integrin recognition is the Arg-Gly-Asp (RGD). Self-assembly offers a unique way of presenting ligands to target receptors for recognition and binding. This study focuses on development of integrin specific peptide amphiphile self-assemblies as carriers for targeted delivery of paclitaxel to αvbeta 3 integrin overexpressing cancers. Amphiphiles composed of conjugates of different analogs of RGD (linear, cyclic or glycosylated) and aliphatic fatty acid with or without 8-amino-3,6-dioxaoctanoic acid (ADA) as linker were synthesized and characterized. The amphiphiles exhibited Critical Micellar Concentration in the range of 7-30 μM. Transmission electron microscopy images revealed the formation of spherical micelles in the size range of 10-40 nm. Forster Resonance Energy Transfer studies revealed entrapment of hydrophobic dyes within a tight micellar core and provided information regarding the cargo exchange within micelles. The RGD micelles exhibited competitive binding with 55% displacement of a bound fluorescent probe by the cyclic RGD micelles. The internalization of fluorescein isothiocynate (FITC) loaded RGD micelles was significantly higher in A2058 melanoma cells compared to free FITC within 20 minutes of incubation at 37°C. The same micelles showed significantly lower internalization at 4°C and on pretreatment with 0.45M sucrose confirming endocytotic uptake of the RGD micellar carriers. The IC50 of paclitaxel in A2058 melanoma cells was lower when treated within RGD micelles as compared to treatment of free drug. On the other hand, IC50 values increased by 2 to 9 fold for micellar treatment

  20. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  1. Targeted drugs in small-cell lung cancer

    PubMed Central

    Daffinà, Maria Grazia; Karachaliou, Niki; González-Cao, Maria; Lazzari, Chiara; Altavilla, Giuseppe; Rosell, Rafael

    2016-01-01

    In contrast to non-small-cell lung cancer (NSCLC), few advances have been made in systemic treatment of small-cell lung cancer (SCLC) in recent years. Most patients are diagnosed with extensive stage disease and are commonly treated with platinum-based chemotherapy which, although attaining high initial objective responses, has a limited impact on survival. Due to the dismal prognosis of SCLC, novel and more effective treatment strategies are urgently needed. A deeper characterization of the genomic landscape of SCLC has led to the development of rational and promising targeted agents. However, despite a large number of clinical trials, results have been disappointing and there are still no approved targeted drugs for SCLC. Recent comprehensive genomic studies suggest SCLC is a heterogeneous disease, characterized by genomic alterations targeting a broad variety of genes, including those involved in transcription regulation and chromatin modification which seem to be a hallmark of this specific lung cancer subtype. Current research efforts are focusing on further understanding of the cellular and molecular abnormalities underlying SCLC development, progression and resistance to chemotherapy. Unraveling the genomic complexity of SCLC could be the key to optimize existing treatments, including chemotherapy and radiotherapy, and for identifying those patients most likely to benefit from selected targeted therapeutic approaches. PMID:26958493

  2. Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

    NASA Astrophysics Data System (ADS)

    Chakkarapani, Prabu; Subbiah, Latha; Palanisamy, Selvamani; Bibiana, Arputha; Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer

    2015-04-01

    We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO3-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO3-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 μm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy.

  3. Vaccines targeting drugs of abuse: is the glass half-empty or half-full?

    PubMed

    Janda, Kim D; Treweek, Jennifer B

    2011-12-16

    The advent of vaccines targeting drugs of abuse heralded a fundamentally different approach to treating substance-related disorders. In contrast to traditional pharmacotherapies for drug abuse, vaccines act by sequestering circulating drugs and terminating the drug-induced 'high' without inducing unwanted neuromodulatory effects. Drug-targeting vaccines have entered clinical evaluation, and although these vaccines show promise from a biomedical viewpoint, the ethical and socioeconomic implications of vaccinating patients against drugs of abuse merit discussion within the scientific community.

  4. Targeted drug delivery and enhanced intracellular release using functionalized liposomes

    NASA Astrophysics Data System (ADS)

    Garg, Ashish

    The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5

  5. The prokaryotic FAD synthetase family: a potential drug target.

    PubMed

    Serrano, Ana; Ferreira, Patricia; Martínez-Júlvez, Marta; Medina, Milagros

    2013-01-01

    Disruption of cellular production of the flavin cofactors, flavin adenine mononucleotide (FMN) and flavin adenine dinucleotide(FAD) will prevent the assembly of a large number of flavoproteins and flavoenzymes involved in key metabolic processes in all types of organisms. The enzymes responsible for FMN and FAD production in prokaryotes and eukaryotes exhibit various structural characteristics to catalyze the same chemistry, a fact that converts the prokaryotic FAD synthetase (FADS) in a potential drug target for the development of inhibitors endowed with anti-pathogenic activity. The first step before searching for selective inhibitors of FADS is to understand the structural and functional mechanisms for the riboflavin kinase and FMN adenylyltransferase activities of the prokaryotic enzyme, and particularly to identify their differential functional characteristics with regard to the enzymes performing similar functions in other organisms, particularly humans. In this paper, an overview of the current knowledge of the structure-function relationships in prokaryotic FADS has been presented, as well as of the state of the art in the use of these enzymes as drug targets.

  6. Tumor Targeting and Drug Delivery by Anthrax Toxin

    PubMed Central

    Bachran, Christopher; Leppla, Stephen H.

    2016-01-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery. PMID:27376328

  7. Potential drug targets for calcific aortic valve disease

    PubMed Central

    Hutcheson, Joshua D.; Aikawa, Elena; Merryman, W. David

    2014-01-01

    Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. We, therefore, discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets. PMID:24445487

  8. AMPA receptors in epilepsy and as targets for antiepileptic drugs.

    PubMed

    Rogawski, M A; Donevan, S D

    1999-01-01

    alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability

  9. Bacterial ghosts as drug carrier and targeting vehicles.

    PubMed

    Huter, V; Szostak, M P; Gampfer, J; Prethaler, S; Wanner, G; Gabor, F; Lubitz, W

    1999-08-27

    A novel system for the packaging of drugs as well as vaccines is presented. Bacterial ghosts are intact, non-denatured bacterial envelopes that are created by lysis of bacteria through the expression of cloned phage PhiX174 gene E. Inhibition of induced E-mediated lysis by MgSO(4), harvesting of cells by centrifugation, and resuspension in low-ionic-strength buffers leads to rapid, violent lysis and results in empty bacterial envelopes with large (approximately 1 microm in diameter) openings. The construction of plasmid pAV1, which encodes a streptavidin fusion protein with an N-terminal membrane anchor sequence, allows the loading of the inner side of the cytoplasmic membrane with streptavidin. The functionality and efficacy of binding of even large biotinylated compounds in such streptavidin ghosts (SA-ghosts) was assessed using the enzyme alkaline phosphatase. The successful binding of biotinylated fluorescent dextran, as well as fluorescent DNA complexed with biotinylated polylysine, was demonstrated microscopically. The display by bacterial ghosts of morphological and antigenic surface structures of their living counterparts permits their attachment to target tissues such as the mucosal surfaces of the gastrointestinal and respiratory tract, and their uptake by phagocytes and M cells. In consequence, SA-ghosts are proposed as drug carriers for site-specific drug delivery.

  10. The prospect of FKBP51 as a drug target.

    PubMed

    Schmidt, Mathias V; Paez-Pereda, Marcelo; Holsboer, Florian; Hausch, Felix

    2012-08-01

    The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51 has repeatedly been associated with emotion processing and numerous stress-related affective disorders. It has also been implicated in contributing to the glucocorticoid hyposensitivity observed in New World primates. More recently, several research groups have consistently shown a protective effect of FKBP51 knockout or knockdown on stress endocrinology and stress-coping behavior in animal models of depression and anxiety. The principal druggability of FKBP51 is exemplified by the prototypic FKBP ligands FK506 and rapamycin. Moreover, FKBP51 is highly suited for X-ray co-crystallography, which should facilitate the rational drug design of improved FKBP51 ligands. In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Nanosized Drug Delivery Systems in Gastrointestinal Targeting: Interactions with Microbiota

    PubMed Central

    Karavolos, Michail; Holban, Alina

    2016-01-01

    The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules. PMID:27690060

  12. Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs.

    PubMed

    Hayashi, Teruo

    2015-01-01

    Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

  13. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    PubMed

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  14. New drugs targeting Th2 lymphocytes in asthma

    PubMed Central

    Caramori, Gaetano; Groneberg, David; Ito, Kazuhiro; Casolari, Paolo; Adcock, Ian M; Papi, Alberto

    2008-01-01

    Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic

  15. The antifungal arsenal: alternative drugs and future targets.

    PubMed

    Wiederhold, Nathan P

    2017-09-07

    Clinically available antifungals for the treatment of invasive fungal infections primarily target either ergosterol in the fungal cell membrane or 1,3-β-D-glucan in the fungal cell wall. These classes include the polyene amphotericin B, the triazoles, and the echinocandins. Although newer antifungals and improved formulations of others have advanced our ability to treat patients with invasive mycoses, these drugs are often limited by toxicities, drug interactions, and the need for intravenous administration. Several investigational agents are currently under development. These include those that also target either ergosterol or 1,3-β-D-glucan but have advantages over currently available drugs. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598 that are more specific for fungal Cyp51 and less so for mammalian CYP 450 enzymes, the echinocandin CD101 that has an extended half-life, and the glucan synthase inhibitor SCY-078, which is being developed for oral administration. In addition, several agents with novel mechanisms of action are also under development. These include the inositol acyltransferase AX001, the dihydroorotate dehydrogenase inhibitor F901318, and VL-2397, which in structure is similar to the siderophore ferrichrome. In addition to possibly overcoming the limitations of currently available antifungals, these newer agents may also be less susceptible to mechanisms of resistance that may render antifungals ineffective. Each of these investigational agents has the potential to improve patient outcomes in the treatment of invasive mycoses. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  16. Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs.

    PubMed

    Takahashi-Nishioka, Tatsuo; Yokogawa, Koichi; Tomatsu, Shunji; Nomura, Masaaki; Kobayashi, Shinjiro; Miyamoto, Ken-Ichi

    2008-03-01

    Site-specific drug delivery to bone is considered to be achievable by utilizing acidic amino acid homopeptides. We found that fluorescence-labeled acidic amino acid (L-Asp or L-Glu) homopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged an enzyme, tissue-nonspecific alkaline phosphatase, to see whether this would improve the efficacy of enzyme replacement therapy. The L-Asp hexapeptide-tagged drugs, including the enzyme, were selectively delivered to bone in comparison with the untagged drugs. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug or enzyme from the acidic oligopeptide. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged estradiol and levofloxacin, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. The adverse effect of estradiol on the uterus was greatly reduced by conjugation to the hexapeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs and enzyme.

  17. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy

    PubMed Central

    Nazıroğlu, Mustafa

    2015-01-01

    Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy Taken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures. PMID:26411767

  18. Blood-brain barrier drug targeting: the future of brain drug development.

    PubMed

    Pardridge, William M

    2003-03-01

    As human longevity increases, the likelihood of the onset of diseases of the brain (and other organs) also increases. Clinical therapeutics offer useful long-term treatments, if not cures, if drugs can be delivered appropriately and effectively. Unfortunately, research in drug transport to the brain has not advanced very far. Through better characterization of the transport systems utilized within the blood-brain barrier, a greater understanding of how to exploit these systems will lead to effective treatments for brain disorders. Pardridge reviews the functions of the various known transport systems in the brain and discusses how the development of BBB drug-targeting programs in pharmaceutical and academic settings may lead to more efficacious treatments.

  19. Polymeric protective agents for nanoparticles in drug delivery and targeting.

    PubMed

    Mogoşanu, George Dan; Grumezescu, Alexandru Mihai; Bejenaru, Cornelia; Bejenaru, Ludovic Everard

    2016-08-30

    Surface modification/functionalization of nanoparticles (NPs) using polymeric protective agents is an issue of great importance and actuality for drug delivery and targeting. Improving the blood circulation half-life of surface-protected nanocarriers is closely related to the elimination of main biological barriers and limiting factors (protein absorption and opsonization), due to the phagocytic activity of reticuloendothelial system. For passive or active targeted delivery, in biomedical area, surface-functionalized NPs with tissue-recognition ligands were designed and optimized as a result of modern research techniques. Also, multi-functionalized nanostructures are characterized by enhanced bioavailability, efficacy, targeted localization, active cellular uptake, and low side effects. Surface-protected NPs are obtained from biocompatible, biodegradable and less toxic natural polymers (dextran, β-cyclodextrin, chitosan, hyaluronic acid, heparin, gelatin) or synthetic polymers, such as poly(lactic acid), poly(lactic-co-glycolic) acid, poly(ε-caprolactone) and poly(alkyl cyanoacrylates). PEGylation is one of the most important functionalization methods providing steric stabilization, long circulating and 'stealth' properties for both polymeric and inorganic-based nanosystems. In addition, for their antimicrobial, antiviral and antitumor effects, cutting-edge researches in the field of pharmaceutical nanobiotechnology highlighted the importance of noble metal (platinum, gold, silver) NPs decorated with biopolymers. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Inducible Mouse Models for Cancer Drug Target Validation

    PubMed Central

    Jeong, Joseph H.

    2016-01-01

    Genetically-engineered mouse (GEM) models have provided significant contributions to our understanding of cancer biology and developing anticancer therapeutic strategies. The development of GEM models that faithfully recapitulate histopathological and clinical features of human cancers is one of the most pressing needs to successfully conquer cancer. In particular, doxycycline-inducible transgenic mouse models allow us to regulate (induce or suppress) the expression of a specific gene of interest within a specific tissue in a temporal manner. Leveraging this mouse model system, we can determine whether the transgene expression is required for tumor maintenance, thereby validating the transgene product as a target for anticancer drug development (target validation study). In addition, there is always a risk of tumor recurrence with cancer therapy. By analyzing recurrent tumors derived from fully regressed tumors after turning off transgene expression in tumor-bearing mice, we can gain an insight into the molecular basis of how tumor cells escape from their dependence on the transgene (tumor recurrence study). Results from such studies will ultimately allow us to predict therapeutic responses in clinical settings and develop new therapeutic strategies against recurrent tumors. The aim of this review is to highlight the significance of doxycycline-inducible transgenic mouse models in studying target validation and tumor recurrence. PMID:28053958

  1. GABAB receptors as drug targets to treat gastroesophageal reflux disease.

    PubMed

    Lehmann, Anders

    2009-06-01

    For many years, acid-suppressive therapy has been at the forefront of treating gastroesophageal reflux disease (GERD), yet despite the advent of the proton pump inhibitors (PPIs) some patients continue to experience persistent GERD symptoms. Therapeutic (non-surgical) options for such patients are currently limited. To tackle this clinical issue, research efforts have begun to focus on 'reflux inhibition' as a potential therapeutic target - i.e. inhibition of transient lower esophageal relaxations (TLESRs), the predominant mechanism of gastroesophageal reflux. Preclinical research has identified a number of drug targets through which TLESRs can be modulated, and the gamma-aminobutyric acid (GABA) type B (GABA(B)) receptor has emerged as one of the most promising. Studies with baclofen, a well-known agonist of this receptor, have demonstrated that reflux inhibition is a valid concept in the clinical setting in that reducing the incidence of TLESRs improves GERD symptoms. But baclofen is associated with significant central nervous system (CNS) side effects, rendering it undesirable for use as a treatment for GERD. Further development work has yielded a number of novel GABA(B) receptor agonists with reduced CNS side effect profiles, and clinical trials are currently being performed with several agents. Compounds that target TLESRs may therefore present a new add-on treatment for patients with persistent GERD symptoms despite PPI therapy.

  2. Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides

    PubMed Central

    Wei, Siau Jia; Chee, Sharon; Yurlova, Larisa; Lane, David; Verma, Chandra; Brown, Christopher; Ghadessy, Farid

    2016-01-01

    Cancer drugs often fail due to the emergence of clinical resistance. This can manifest through mutations in target proteins that selectively exclude drug binding whilst retaining aberrant function. A priori knowledge of resistance-inducing mutations is therefore important for both drug design and clinical surveillance. Stapled peptides represent a novel class of antagonists capable of inhibiting therapeutically relevant protein-protein interactions. Here, we address the important question of potential resistance to stapled peptide inhibitors. HDM2 is the critical negative regulator of p53, and is often overexpressed in cancers that retain wild-type p53 function. Interrogation of a large collection of randomly mutated HDM2 proteins failed to identify point mutations that could selectively abrogate binding by a stapled peptide inhibitor (PM2). In contrast, the same interrogation methodology has previously uncovered point mutations that selectively inhibit binding by Nutlin, the prototypical small molecule inhibitor of HDM2. Our results demonstrate both the high level of structural p53 mimicry employed by PM2 to engage HDM2, and the potential resilience of stapled peptide antagonists to mutations in target proteins. This inherent feature could reduce clinical resistance should this class of drugs enter the clinic. PMID:27057630

  3. Schizophrenia drug discovery and development in an evolving era: are new drug targets fulfilling expectations?

    PubMed

    Dunlop, John; Brandon, Nicholas J

    2015-02-01

    Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.

  4. New approaches for the identification of drug targets in protozoan parasites.

    PubMed

    Müller, Joachim; Hemphill, Andrew

    2013-01-01

    Antiparasitic chemotherapy is an important issue for drug development. Traditionally, novel compounds with antiprotozoan activities have been identified by screening of compound libraries in high-throughput systems. More recently developed approaches employ target-based drug design supported by genomics and proteomics of protozoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed. The gene-expression machinery has been among the first targets for antiparasitic drugs and is still under investigation as a target for novel compounds. Other targets include cytoskeletal proteins, proteins involved in intracellular signaling, membranes, and enzymes participating in intermediary metabolism. In apicomplexan parasites, the apicoplast is a suitable target for established and novel drugs. Some drugs act on multiple subcellular targets. Drugs with nitro groups generate free radicals under anaerobic growth conditions, and drugs with peroxide groups generate radicals under aerobic growth conditions, both affecting multiple cellular pathways. Mefloquine and thiazolides are presented as examples for antiprotozoan compounds with multiple (side) effects. The classic approach of drug discovery employing high-throughput physiological screenings followed by identification of drug targets has yielded the mainstream of current antiprotozoal drugs. Target-based drug design supported by genomics and proteomics of protozoan parasites has not produced any antiparasitic drug so far. The reason for this is discussed and a synthesis of both methods is proposed. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Mining significant substructure pairs for interpreting polypharmacology in drug-target network.

    PubMed

    Takigawa, Ichigaku; Tsuda, Koji; Mamitsuka, Hiroshi

    2011-02-23

    A current key feature in drug-target network is that drugs often bind to multiple targets, known as polypharmacology or drug promiscuity. Recent literature has indicated that relatively small fragments in both drugs and targets are crucial in forming polypharmacology. We hypothesize that principles behind polypharmacology are embedded in paired fragments in molecular graphs and amino acid sequences of drug-target interactions. We developed a fast, scalable algorithm for mining significantly co-occurring subgraph-subsequence pairs from drug-target interactions. A noteworthy feature of our approach is to capture significant paired patterns of subgraph-subsequence, while patterns of either drugs or targets only have been considered in the literature so far. Significant substructure pairs allow the grouping of drug-target interactions into clusters, covering approximately 75% of interactions containing approved drugs. These clusters were highly exclusive to each other, being statistically significant and logically implying that each cluster corresponds to a distinguished type of polypharmacology. These exclusive clusters cannot be easily obtained by using either drug or target information only but are naturally found by highlighting significant substructure pairs in drug-target interactions. These results confirm the effectiveness of our method for interpreting polypharmacology in drug-target network.

  6. Advanced drug delivery and targeting technologies for the ocular diseases

    PubMed Central

    Barar, Jaleh; Aghanejad, Ayuob; Fathi, Marziyeh; Omidi, Yadollah

    2016-01-01

    Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies

  7. Scientometrics of drug discovery efforts: pain-related molecular targets.

    PubMed

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I-III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I-II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009-2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004-2008 period. In addition, publications representing Phase I-III trials of investigational drugs (2009-2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics, when its

  8. Scientometrics of drug discovery efforts: pain-related molecular targets

    PubMed Central

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I–III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I–II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009–2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004–2008 period. In addition, publications representing Phase I–III trials of investigational drugs (2009–2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics

  9. Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

    PubMed Central

    Pierce, Christopher G.; Lopez-Ribot, Jose L.

    2014-01-01

    Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751

  10. Targeting RSV with Vaccines and Small Molecule Drugs

    PubMed Central

    Costello, Heather M.; Ray, William C.; Chaiwatpongsakorn, Supranee; Peeples, Mark E.

    2012-01-01

    Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates. PMID:22335496

  11. Possibilities of acoustic thermometry for controlling targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Anosov, A. A.; Nemchenko, O. Yu.; Less, Yu. A.; Kazanskii, A. S.; Mansfel'd, A. D.

    2015-07-01

    Model acoustic thermometry experiments were conducted during heating of an aqueous liposome suspension. Heating was done to achieve the liposome phase transition temperature. At the moment of the phase transition, the thermal acoustic signal achieved a maximum and decreased, despite continued heating. During subsequent cooling of the suspension, when lipids again passed through the phase transition point, the thermal acoustic signal again increased, despite a reduction in temperature. This effect is related to an increase in ultrasound absorption by the liposome suspension at the moment of the lipid phase transition. The result shows that acoustic thermography can be used to control targeted delivery of drugs mixed in thermally sensitive liposomes, the integrity of which is violated during heating to the phase transition temperature.

  12. Autophagy modulation as a target for anticancer drug discovery

    PubMed Central

    Li, Xin; Xu, Huai-long; Liu, Yong-xi; An, Na; Zhao, Si; Bao, Jin-ku

    2013-01-01

    Autophagy, an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been implicated in diverse diseases including cancer. Autophagy can function as either a promoter or a suppressor of cancer, which makes it a promising and challenging therapeutic target. Herein, we overview the regulatory mechanisms and dual roles of autophagy in cancer. We also describe some of the representative agents that exert their anticancer effects by regulating autophagy. Additionally, some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery. In summary, these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements. PMID:23564085

  13. Functional dyspepsia: drugs for new (and old) therapeutic targets.

    PubMed

    Cremonini, Filippo; Delgado-Aros, Silvia; Talley, Nicholas J

    2004-08-01

    The therapeutic management of functional dyspepsia remains a major challenge for the gastroenterologist. Current therapies available are based on putative underlying pathophysiologic mechanisms, including gastric acid sensitivity, slow gastric emptying and Helicobacter pylori infection, but only a small proportion of patients achieve symptomatic benefit from these therapeutic approaches. Relatively novel mechanistic concepts under testing include impaired gastric accomodation, visceral hypersensitivity, and central nervous system dysfunction. Serotonergic modulators (e.g. the 5-HT4 agonist tegaserod, the 5-HT3 antagonist alosetron and the 5-HT1P agonist sumatriptan), CCK-1 antagonists (e.g. dexloxiglumide), opioid agonists (e.g. asimadoline), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g dextromethorphan), neurokinin antagonists (e.g. talnetant), capsaicin-like agents and antidepressants are among the agents currently under investigation. It seems unlikely, however, that targeting a single mechanism with an individual drug will result in complete symptom remission in most cases.

  14. Alzheimer's associated inflammation, potential drug targets and future therapies.

    PubMed

    Stuchbury, G; Münch, G

    2005-03-01

    Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants.

  15. Current drug treatments targeting dopamine D3 receptor.

    PubMed

    Leggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, Filippo

    2016-09-01

    Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiological effects. D3R is involved in a number of pathological conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homology shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [(11)C]-(+)-PHNO for positron emission tomography studies in animal models as well as in humans, allows researchers to estimate the expression of D3R in vivo; displacement of [(11)C]-(+)-PHNO binding by concurrent drug treatments is used to estimate the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacological therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role.

  16. Mycobacterium tuberculosis DNA gyrase as a target for drug discovery.

    PubMed

    Mdluli, Khisimuzi; Ma, Zhenkun

    2007-06-01

    Bacterial DNA gyrase is an important target of antibacterial agents, including fluoroquinolones. In most bacterial species, fluoroquinolones inhibit DNA gyrase and topoisomerase IV and cause bacterial cell-death. Other naturally occurring bacterial DNA gyrase inhibitors, such as novobiocin, are also known to be effective as antibacterial agents. DNA gyrase is an ATP-dependent enzyme that acts by creating a transient double-stranded DNA break. It is unique in catalyzing the negative supercoiling of DNA and is essential for efficient DNA replication, transcription, and recombination. DNA gyrase is a tetrameric A2B2 protein. The A subunit carries the breakage-reunion active site, whereas the B subunit promotes ATP hydrolysis. The M. tuberculosis genome analysis has identified a gyrB-gyrA contig in which gyrA and gyrB encode the A and B subunits, respectively. There is no evidence that M. tuberculosis has homologs of the topoisomerase IV, parC and parE genes, which are present in most other bacteria. Newer fluoroquinolones, including moxifloxacin and gatifloxacin, exhibit potent activity against M. tuberculosis, and show potential to shorten the duration for TB treatment. Resistance to fluoroquinolones remains uncommon in clinical isolates of M. tuberculosis. M. tuberculosis DNA gyrase is thus a validated target for anti-tubercular drug discovery. Inhibitors of this enzyme are also active against non-replicating mycobacteria, which might be important for the eradication of persistent organisms. A novel inhibitor of M. tuberculosis DNA gyrase would be effective against multi-drug resistant (MDR)-TB, and it could also be effective against fluoroquinolone-resistant M. tuberculosis.

  17. Peptide-drug conjugate linked via a disulfide bond for kidney targeted drug delivery.

    PubMed

    Geng, Qian; Sun, Xun; Gong, Tao; Zhang, Zhi-Rong

    2012-06-20

    Chronic kidney disease (CKD) is a worldwide public health problem, and unfortunately, the therapeutic index of clinically available drugs is limited. Thus, there is a great need to exploit effective treatment strategies, and the carrier-drug approach is an attractive method to improve the kidney specificity of the therapeutic agents. The aim of this present study is to develop a peptide-drug conjugate for the kidney targeted delivery of angiotensin-converting enzyme (ACE) inhibitor captopril (CAP), since G3-C12 peptide (ANTPCGPYTHDCPVKR) could specifically accumulate in the kidney after intravenous injection. Therefore, FITC labeled G3-C12 peptide (G3-C12-FITC) and peptide-drug conjugate (G3-C12-CAP) with a disulfide bond which can be cleaved by reduced glutathione in the kidney were prepared by solid-phase peptide synthesis. The fluorescence imaging of G3-C12-FITC revealed that the labeled peptide specifically accumulated in the kidney soon after i.v. injection to mice, and the accumulation is due largely to the reabsorption of the peptide by the proximal renal tubule cells. Furthermore, in comparison with the corresponding nonconjugated form, a 2.7-fold increase in renal area under concentration-time curve produced by the conjugate was observed in mice. Interestingly, the CAP entirely released in the kidney even at 0.05 h postinjection through disulfide reduction. As a consequence, the in vivo renal ACE inhibition was significantly increased. In conclusion, these findings suggest the potential of G3-C12 peptide serving as a suitable candidate carrier for kidney-targeted drug delivery.

  18. Molecular Targets of Opiate Drug Abuse in NeuroAIDS

    PubMed Central

    Hauser, Kurt F.; El-Hage, Nazira; Buch, Shreya; Berger, Joseph R.; Tyor, William R.; Nath, Avindra; Bruce-Keller, Annadora J.; Knapp, Pamela E.

    2015-01-01

    Opiate drug abuse, through selective actions at μ opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiate drugs have some affinity for κ (KOR) and/or δ (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS. PMID:16260386

  19. Modern prodrug design for targeted oral drug delivery.

    PubMed

    Dahan, Arik; Zimmermann, Ellen M; Ben-Shabat, Shimon

    2014-10-14

    The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  20. TRPV1: A Potential Drug Target for Treating Various Diseases

    PubMed Central

    Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

    2014-01-01

    Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically. PMID:24861977

  1. Discovery of the target for immunomodulatory drugs (IMiDs).

    PubMed

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2016-05-01

    Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity. Recently, new thalidomide derivatives, called immunomodulatory drugs (IMiDs), have been developed by Celgene. Among them, lenalidomide (Len) and pomalidomide (Pom) were shown to exert strong therapeutic effects against MM. It was found that Len and Pom both bind CRBN-CRL4 and recruit neomorphic substrates (Ikaros and Aiolos). More recently it was reported that casein kinase 1a (Ck1a) was identified as a substrate for CRBN-CRL4 in the presence of Len, but not Pom. Ck1a breakdown explains why Len is specifically effective for myelodysplastic syndrome with 5q deletion. It is now proposed that binding of IMiDs to CRBN appears to alter the substrate specificity of CRBN-CRL4. In this review, we introduce recent findings on IMiDs.

  2. Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

    PubMed Central

    Moreno, Miguel Angel; Alonso, Ana; Alcolea, Pedro Jose; Abramov, Ariel; de Lacoba, Mario García; Abendroth, Jan; Zhang, Sunny; Edwards, Thomas; Lorimer, Don; Myler, Peter John; Larraga, Vicente

    2014-01-01

    Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT) has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs. PMID:25516846

  3. Shikimate kinase, a protein target for drug design.

    PubMed

    Coracini, J D; de Azevedo, W F

    2014-01-01

    ATP: shikimate 3-phosphotransferase catalyzes the fifth chemical reaction of shikimate pathway. This metabolic route is responsible for the production of chorismate, a precursor of aromatic amino acids. This especially interesting enzymatic step is indispensable for the survival of the etiological agent of tuberculosis and not found in animals. Therefore the enzyme ATP: shikimate 3-phosphotransferase has been classified as a target for chemotherapeutic development of antitubercular drugs. The ATP:shikimate 3-phosphotransferase has also the denomination of shikimate kinase. This review highlights the available crystallographic studies of shikimate kinases that have been used to identify structural features for ligand-biding affinity. We also describe molecular docking studies focused on shikimate kinase. These computational studies were performed in order to identify the new generation of antitubercular drugs and several potential inhibitors have been described. In addition, a structural comparison of shikimate kinase ATP-binding pocket with human cyclin-dependent kinase 2 (CDK2) is described. This analysis shows the structural similarities between both enzymes, and the potential beneficial aspects of abundant structural studies of CDK2 and their inhibitors to bring further understanding of the ligand-binding specificity for shikimate kinase.

  4. Target-Based Drug Repositioning Using Large-Scale Chemical-Protein Interactome Data.

    PubMed

    Sawada, Ryusuke; Iwata, Hiroaki; Mizutani, Sayaka; Yamanishi, Yoshihiro

    2015-12-28

    Drug repositioning, or the identification of new indications for known drugs, is a useful strategy for drug discovery. In this study, we developed novel computational methods to predict potential drug targets and new drug indications for systematic drug repositioning using large-scale chemical-protein interactome data. We explored the target space of drugs (including primary targets and off-targets) based on chemical structure similarity and phenotypic effect similarity by making optimal use of millions of compound-protein interactions. On the basis of the target profiles of drugs, we constructed statistical models to predict new drug indications for a wide range of diseases with various molecular features. The proposed method outperformed previous methods in terms of interpretability, applicability, and accuracy. Finally, we conducted a comprehensive prediction of the drug-target-disease association network for 8270 drugs and 1401 diseases and showed biologically meaningful examples of newly predicted drug targets and drug indications. The predictive model is useful to understand the mechanisms of the predicted drug indications.

  5. Genome-Wide Identification of Potential Drug Target in Enterobacteriaceae Family: A Homology-Based Method.

    PubMed

    Hadizadeh, Morteza; Tabatabaiepour, Seyyede Nasim; Tabatabaiepour, Seyyede Zahra; Hosseini Nave, Hossein; Mohammadi, Mohsen; Sohrabi, Seyyed Mohsen

    2017-05-18

    The Enterobacteriaceae is a large family of Gram-negative, facultative anaerobic, non-spore forming rod-shaped bacteria that includes harmless and pathogenic organisms. The emergence and development of drug resistance in Enterobacteriaceae is complicating the treatment of serious infections. The aim of this study is to predict and characterize putative drug targets in Enterobacteriaceae family employing a homology-based computational method. The final putative drug targets were qualitatively characterized via cellular function prediction, subcellular localization prediction, broad-spectrum, and druggability analyses. Of 6,327 analyzed proteins, 35 proteins were selected as final putative drug targets in Enterobacteriaceae family. These putative drug targets were involved in different vital pathways like metabolism, biosynthesis of macromolecule, and cell division. Predicted drug targets were also localized in the cytoplasm and cytoplasmic membrane of the pathogen that acts as antimicrobial or vaccine targets. Of 35 drug targets, 5 targets were druggable and 30 targets were not druggable and were predicted as novel drug targets, which should be further evaluated to develop new antimicrobial. Thirteen drug targets were considered as broad-spectrum targets. It is expected that results of our study could facilitate the production of novel antibacterial for efficient treatment of infections caused by Enterobacteriaceae pathogens.

  6. Targeting memory processes with drugs to prevent or cure PTSD.

    PubMed

    Cain, Christopher K; Maynard, George D; Kehne, John H

    2012-09-01

    Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment.

  7. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    PubMed

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  8. Optimized shapes of magnetic arrays for drug targeting applications

    NASA Astrophysics Data System (ADS)

    Barnsley, Lester C.; Carugo, Dario; Stride, Eleanor

    2016-06-01

    Arrays of permanent magnet elements have been utilized as light-weight, inexpensive sources for applying external magnetic fields in magnetic drug targeting applications, but they are extremely limited in the range of depths over which they can apply useful magnetic forces. In this paper, designs for optimized magnet arrays are presented, which were generated using an optimization routine to maximize the magnetic force available from an arbitrary arrangement of magnetized elements, depending on a set of design parameters including the depth of targeting (up to 50 mm from the magnet) and direction of force required. A method for assembling arrays in practice is considered, quantifying the difficulty of assembly and suggesting a means for easing this difficulty without a significant compromise to the applied field or force. Finite element simulations of in vitro magnetic retention experiments were run to demonstrate the capability of a subset of arrays to retain magnetic microparticles against flow. The results suggest that, depending on the choice of array, a useful proportion of particles (more than 10% ) could be retained at flow velocities up to 100 mm s-1 or to depths as far as 50 mm from the magnet. Finally, the optimization routine was used to generate a design for a Halbach array optimized to deliver magnetic force to a depth of 50 mm inside the brain.

  9. PEPTIDE TARGETING OF PLATINUM ANTI-CANCER DRUGS

    PubMed Central

    Ndinguri, Margaret W.; Solipuram, Rajasree; Gambrell, Robert P.; Aggarwal, Sita; Hansel, William; Hammer, Robert P.

    2009-01-01

    Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg-CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is non toxic and highly soluble in water. Platinum conjugates synthesized using the pegylated peptides are also water soluble with reduced or eliminated peptide immunogenicity. The choice of carboplatin as our untargeted platinum complex was due to the fact that malonate linker chelates platinum in a manner similar to carboplatin. Cell toxicity assay and competition assay on the PC-3 cells (CD13 positive receptors) revealed selective delivery and destruction of PC-3 cells using targeted Pt-peptide conjugates 7 and 8 significantly more than untargeted carboplatin. Platinum uptake on PC-3 cells was 12-fold more for conjugate 7 and 3-fold more for conjugate 8 compared to the untargeted carboplatin indicating selectively activation of the CD13 receptors and delivery of the conjugates to CD13 positive cells. Further analysis on effects of conjugates 7 and 8 on PC-3 cells using caspase-3/7, fluorescence microscopy and DNA fragmentation confirmed that the cells were dying by apoptosis. PMID:19775102

  10. The Food and Drug Addiction Epidemic: Targeting Dopamine Homeostasis.

    PubMed

    Blum, Kenneth; Thanos, Panayotis K; Wang, Gene-Jack; Febo, Marcelo; Demetrovics, Zsolt; Modestino, Edward Justin; Braverman, Eric R; Baron, David; Badgaiyan, Rajendra D; Gold, Mark S

    2017-08-22

    Obesity is damaging the lives of more than 300 million people worldwide and maintaining a healthy weight using popular weight loss tactics remains a very difficult undertaking. Managing the obesity problem seems within reach, as better understanding develops, of the function of our genome in drug/nutrient responses. Strategies indicated by this understanding of nutriepigenomics and neurogenetics in the treatment and prevention of metabolic syndrome and obesity include moderation of mRNA expression by DNA methylation, and inhibition of histone deacetylation. Based on an individual's genetic makeup deficient metabolic pathways can be targeted epigenetically by, for example, the provision of dietary supplementation that includes phytochemicals, vitamins, and importantly functional amino acids. Also, the chromatin structure of imprinted genes that control nutrients during fetal development can be modified. Pathways affecting dopamine signaling, molecular transport and nervous system development are implicated in these strategies. Obesity is a subtype of Reward Deficiency Syndrome (RDS) and these new strategies in the treatment and prevention of obesity target improved dopamine function. It is not merely a matter of gastrointestinal signaling linked to hypothalamic peptides, but alternatively, finding novel ways to improve ventral tegmental area (VTA) dopaminergic function and homeostasis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Targeting memory processes with drugs to prevent or cure PTSD

    PubMed Central

    Cain, Christopher K.; Maynard, George D.; Kehne, John H.

    2015-01-01

    Introduction Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. Areas covered Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. Expert opinion Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment. PMID:22834476

  12. The Gastric H,K ATPase as a Drug Target

    PubMed Central

    Sachs, George; Shin, Jai Moo; Vagin, Olga; Lambrecht, Nils; Yakubov, Iskandar; Munson, Keith

    2010-01-01

    The recent progress in therapy if acid disease has relied heavily on the performance of drugs targeted against the H,K ATPase of the stomach and the H2 receptor antagonists. It has become apparent in the last decade that the proton pump is the target that has the likelihood of being the most sustainable area of therapeutic application in the regulation of acid suppression. The process of activation of acid secretion requires a change in location of the ATPase from cytoplasmic tubules into the microvilli of the secretory canaliculus of the parietal cell. Stimulation of the resting parietal cell, with involvement of F-actin and ezrin does not use significant numbers of SNARE proteins, because their message is depleted in the pure parietal cell transcriptome. The cell morphology and gene expression suggest a tubule fusion-eversion event. As the active H,K ATPase requires efflux of KCl for activity we have, using the transcriptome derived from 99% pure parietal cells and immunocytochemistry, provided evidence that the KCl pathway is mediated by a KCQ1/KCNE2 complex for supplying K+ and CLIC6 for supplying the accompanying Cl−. The pump has been modeled on the basis of the structures of different conformations of the sr Ca ATPase related to the catalytic cycle. These models use the effects of site directed mutations and identification of the binding domain of the K competitive acid pump antagonists or the defined site of binding for the covalent class of proton pump inhibitors. The pump undergoes conformational changes associated with phosphorylation to allow the ion binding site to change exposure from cytoplasmic to luminal exposure. We have been able to postulate that the very low gastric pH is achieved by lysine 791 motion extruding the hydronium ion bound to carboxylates in the middle of the membrane domain. These models also allow description of the K+ entry to form the K+ liganded form of the enzyme and the reformation of the ion site inward conformation thus

  13. Retention of ferrofluid aggregates at the target site during magnetic drug targeting

    NASA Astrophysics Data System (ADS)

    Asfer, Mohammed; Saroj, Sunil Kumar; Panigrahi, Pradipta Kumar

    2017-08-01

    The present study reports the retention dynamics of a ferrofluid aggregate localized at the target site inside a glass capillary (500 × 500 μm2 square cross section) against a bulk flow of DI water (Re = 0.16 and 0.016) during the process of magnetic drug targeting (MDT). The dispersion dynamics of iron oxide nanoparticles (IONPs) into bulk flow for different initial size of aggregate at the target site is reported using the brightfield visualization technique. The flow field around the aggregate during the retention is evaluated using the μPIV technique. IONPs at the outer boundary experience a higher shear force as compared to the magnetic force, resulting in dispersion of IONPs into the bulk flow downstream to the aggregate. The blockage effect and the roughness of the outer boundary of the aggregate resulting from chain like clustering of IONPs contribute to the flow recirculation at the downstream region of the aggregate. The entrapment of seeding particles inside the chain like clusters of IONPs at the outer boundary of the aggregate reduces the degree of roughness resulting in a streamlined aggregate at the target site at later time. The effect of blockage, structure of the aggregate, and disturbed flow such as recirculation around the aggregate are the primary factors, which must be investigated for the effectiveness of the MDT process for in vivo applications.

  14. PBIT: pipeline builder for identification of drug targets for infectious diseases.

    PubMed

    Shende, Gauri; Haldankar, Harshala; Barai, Ram Shankar; Bharmal, Mohammed Husain; Shetty, Vinit; Idicula-Thomas, Susan

    2016-12-30

    PBIT (Pipeline Builder for Identification of drug Targets) is an online webserver that has been developed for screening of microbial proteomes for critical features of human drug targets such as being non-homologous to human proteome as well as the human gut microbiota, essential for the pathogen's survival, participation in pathogen-specific pathways etc. The tool has been validated by analyzing 57 putative targets of Candida albicans documented in literature. PBIT integrates various in silico approaches known for drug target identification and will facilitate high-throughput prediction of drug targets for infectious diseases, including multi-pathogenic infections.

  15. A comparative study of disease genes and drug targets in the human protein interactome

    PubMed Central

    2015-01-01

    Background Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. Results In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. Conclusions The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing. PMID:25861037

  16. A comparative study of disease genes and drug targets in the human protein interactome.

    PubMed

    Sun, Jingchun; Zhu, Kevin; Zheng, W; Xu, Hua

    2015-01-01

    Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.

  17. Two-stage flux balance analysis of metabolic networks for drug target identification

    PubMed Central

    2011-01-01

    Background Efficient identification of drug targets is one of major challenges for drug discovery and drug development. Traditional approaches to drug target identification include literature search-based target prioritization and in vitro binding assays which are both time-consuming and labor intensive. Computational integration of different knowledge sources is a more effective alternative. Wealth of omics data generated from genomic, proteomic and metabolomic techniques changes the way researchers view drug targets and provides unprecedent opportunities for drug target identification. Results In this paper, we develop a method based on flux balance analysis (FBA) of metabolic networks to identify potential drug targets. This method consists of two linear programming (LP) models, which first finds the steady optimal fluxes of reactions and the mass flows of metabolites in the pathologic state and then determines the fluxes and mass flows in the medication state with the minimal side effect caused by the medication. Drug targets are identified by comparing the fluxes of reactions in both states and examining the change of reaction fluxes. We give an illustrative example to show that the drug target identification problem can be solved effectively by our method, then apply it to a hyperuricemia-related purine metabolic pathway. Known drug targets for hyperuricemia are correctly identified by our two-stage FBA method, and the side effects of these targets are also taken into account. A number of other promising drug targets are found to be both effective and safe. Conclusions Our method is an efficient procedure for drug target identification through flux balance analysis of large-scale metabolic networks. It can generate testable predictions, provide insights into drug action mechanisms and guide experimental design of drug discovery. PMID:21689470

  18. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    PubMed Central

    Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

    2014-01-01

    Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

  19. Halogen bond: its role beyond drug-target binding affinity for drug discovery and development.

    PubMed

    Xu, Zhijian; Yang, Zhuo; Liu, Yingtao; Lu, Yunxiang; Chen, Kaixian; Zhu, Weiliang

    2014-01-27

    Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.

  20. Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

    PubMed Central

    Pastor-Anglada, Marçal; Pérez-Torras, Sandra

    2015-01-01

    Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters. PMID:25713533

  1. DrugE-Rank: improving drug–target interaction prediction of new candidate drugs or targets by ensemble learning to rank

    PubMed Central

    Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

    2016-01-01

    Motivation: Identifying drug–target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug–target interactions of new candidate drugs or targets. Methods: Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. Results: The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. Availability: http://datamining-iip.fudan.edu.cn/service/DrugE-Rank Contact: zhusf@fudan.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307615

  2. A two-step similarity-based method for prediction of drug's target group.

    PubMed

    Chen, Lei; Zeng, Wei-Ming

    2013-03-01

    Determination of drug's target protein is very important for studying drug-target interaction network, while drug-target interaction network is a key area in the drug discovery pipeline. Thus correct prediction of drug's target protein is very helpful to promote the development of drug discovery. In this study, we developed a two-step similarity-based method to predict drug's target group. In each step, a similarity score (obtained by graph representation in the first step, and chemical functional group representation in the second step) was employed to make prediction. Since some drugs can target proteins distributing in more than one group of proteins, the method provided a series of candidate target groups for each drug. As a result, the first-order prediction accuracy on training set and test set were 79.01% and 76.43%, respectively, which were much higher than the success rate of a random guess. The results show that using graph representation to encode drug is a good choice in this area. We expect that this contribution will provide some help to understand drug-target interaction network.

  3. Aurora kinase family: a new target for anticancer drug.

    PubMed

    Macarulla, Teresa; Ramos, Francisco Javier; Tabernero, Josep

    2008-06-01

    Aurora kinases (AK) are the name given to a family of Serine/threonine (Ser/Thr) protein kinases. These proteins represent a novel family of kinases crucial for cell cycle control. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatics into two daughters cells. It is a complex biologic process, and errors in this mechanism can lead to genomic instability, a condition associated with tumorigenesis. This process is tightly regulated by several proteins, some of them acting as check-points that ultimately ensure the correct temporal and spatial coordination of this critical biologic process. Among this network of mitotic regulators, AK play a critical role in cellular division by controlling chromatid segregation. Three AK family members have been identified in mammalian cells: A, B, and C. These proteins are implicated in several vital events in mitosis. In experimental models, overexpression of AK can induce spindle defects, chromosome mis-segregation, and malignant transformation. Conversely, downregulation of AK expression cause mitotic arrest and apoptosis in tumor cell lines. The expression levels of human AK are increased in certain types of cancer including breast, colon, pancreatic, ovarian, and gastric tumors. This observation has lent an interest to this family of kinases as potential drug targets for development of new anticancer therapies. This review focuses in recent progress in the role of AK in tumorogenesis and the development of new anticancer drug against AK proteins. This manuscript also includes some relevant patents as well.

  4. NRDTD: a database for clinically or experimentally supported non-coding RNAs and drug targets associations

    PubMed Central

    Sun, Ya-Zhou; Zhang, De-Hong; Yan, Gui-Ying; An, Ji-Yong; You, Zhu-Hong

    2017-01-01

    Abstract In recent years, more and more non-coding RNAs (ncRNAs) have been identified and increasing evidences have shown that ncRNAs may affect gene expression and disease progression, making them a new class of targets for drug discovery. It thus becomes important to understand the relationship between ncRNAs and drug targets. For this purpose, an ncRNAs and drug targets association database would be extremely beneficial. Here, we developed ncRNA Drug Targets Database (NRDTD) that collected 165 entries of clinically or experimentally supported ncRNAs as drug targets, including 97 ncRNAs and 96 drugs. Moreover, we annotated ncRNA-drug target associations with drug information from KEGG, PubChem, DrugBank, CTD or Wikipedia, GenBank sequence links, OMIM disease ID, pathway and function annotation for ncRNAs, detailed description of associations between ncRNAs and diseases from HMDD or LncRNADisease and the publication PubMed ID. Additionally, we provided users a link to submit novel disease-ncRNA-drug associations and corresponding supporting evidences into the database. We hope NRDTD will be a useful resource for investigating the roles of ncRNAs in drug target identification, drug discovery and disease treatment. Database URL: http://chengroup.cumt.edu.cn/NRDTD

  5. Collagen like peptide bioconjugates for targeted drug delivery applications

    NASA Astrophysics Data System (ADS)

    Luo, Tianzhi

    the coil/globule conformational transition of the PDEGMEMA building block above its LCST with stabilization of the nanostructures by the hydrophilic CLP. To the best of our knowledge, this is the first report on such assembled nanostructures from collagen-like peptide containing copolymers. Due to the strong propensity for CLPs to bind to natural collagen via strand invasion processes, these nanosized vesicles may be used as drug carriers for targeted delivery. In addition to synthetic polymers, the collagen like peptide is then conjugated with a thermoresponsive elastin-like peptide (ELP). The resulting ELP-CLP diblock conjugates show a remarkable reduction in the inverse transition temperature of the ELP domain, attributed to the anchoring effect of the CLP triple helix. The lower transition temperature of the conjugate enables facile formation of well-defined vesicles at physiological temperature and the unexpected resolubilization of the vesicles at elevated temperatures upon unfolding of the CLP domain. Given the ability of CLPs to modify collagens, this work provides not only a simple and versatile avenue for controlling the inverse transition behavior of elastin-like peptides, but also suggest future opportunities for these thermoresponsive nanostructures in biologically relevant environments. In the last section, the potential of using the ELP-CLP nanoparticles as drug delivery vehicles for targeting collagen containing matrices is evaluated. A sustained release of clinically relevant amount of encapsulated modelled drug is achieved within three weeks, followed by a thermally controlled burst release. As expected, the ELP-CLP nanoparticles show strong retention on collagen substrate, via specific binding through collagen triple helix hybridization. Additionally, cell viability and proliferation studies using fibroblasts and chondrocytes suggest the nanoparticles are non-cytotoxic. Additionally, almost no TNF-alpha expression from macrophages is observed

  6. The Antihelmintic Drug Pyrvinium Pamoate Targets Aggressive Breast Cancer

    PubMed Central

    Xu, Wei; Lacerda, Lara; Debeb, Bisrat G.; Atkinson, Rachel L.; Solley, Travis N.; Li, Li; Orton, Darren; McMurray, John S.; Hang, Brian I.; Lee, Ethan; Klopp, Ann H.; Ueno, Naoto T.; Reuben, James M.; Krishnamurthy, Savitri; Woodward, Wendy A.

    2013-01-01

    WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted. PMID:24013655

  7. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets

    PubMed Central

    Supuran, Claudiu T.

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3) × 105 s−1 and kcat/KM values of (4.7–8.5) × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3–90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2–88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. PMID:27322334

  8. In vivo imaging of specific drug target binding at subcellular resolution

    PubMed Central

    Dubach, J.M.; Vinegoni, C.; Mazitschek, R.; Fumene Feruglio, P.; Cameron, L.A.; Weissleder, R.

    2015-01-01

    The possibility to measure binding of small molecule drugs to desired targets in live cells could provide a better understanding of drug action. However, current approaches mostly yield static data, require lysis or rely on indirect assays and thus often provide an incomplete understanding of drug action. Here, we present a multiphoton fluorescence anisotropy microscopy live cell imaging technique to measure and map drug-target interaction in real time at subcellular resolution. This approach is generally applicable using any fluorescently labeled drug and enables high resolution spatial and temporal mapping of bound and unbound drug distribution. To illustrate our approach we measure intracellular target engagement of the chemotherapeutic Olaparib, a poly(ADP-ribose) polymerase inhibitor, in live cells and within a tumor in vivo. These results are the first generalizable approach to directly measure drug-target binding in vivo and present a promising tool to enhance understanding of drug activity. PMID:24867710

  9. In vivo imaging of specific drug-target binding at subcellular resolution

    NASA Astrophysics Data System (ADS)

    Dubach, J. M.; Vinegoni, C.; Mazitschek, R.; Fumene Feruglio, P.; Cameron, L. A.; Weissleder, R.

    2014-05-01

    The possibility of measuring binding of small-molecule drugs to desired targets in live cells could provide a better understanding of drug action. However, current approaches mostly yield static data, require lysis or rely on indirect assays and thus often provide an incomplete understanding of drug action. Here, we present a multiphoton fluorescence anisotropy microscopy live cell imaging technique to measure and map drug-target interaction in real time at subcellular resolution. This approach is generally applicable using any fluorescently labelled drug and enables high-resolution spatial and temporal mapping of bound and unbound drug distribution. To illustrate our approach we measure intracellular target engagement of the chemotherapeutic Olaparib, a poly(ADP-ribose) polymerase inhibitor, in live cells and within a tumour in vivo. These results are the first generalizable approach to directly measure drug-target binding in vivo and present a promising tool to enhance understanding of drug activity.

  10. RFDT: A Rotation Forest-based Predictor for Predicting Drug-Target Interactions using Drug Structure and Protein Sequence Information.

    PubMed

    Wang, Lei; You, Zhu-Hong; Chen, Xing; Yan, Xin; Liu, Gang; Zhang, Wei

    2016-11-14

    Identification of interaction between drugs and target proteins plays an important role in discovering new drug candidates. However, through the experimental method to identify the drug-target interactions remain to be extremely time-consuming, expensive and challenging even nowadays. Therefore, it is urgent to develop new computational methods to predict potential drug-target interactions (DTI). In this article, a novel computational model is developed for predicting potential drug-target interactions under the theory that each drug-target interaction pair can be represented by the structural properties from drugs and evolutionary information derived from proteins. Specifically, the protein sequences are encoded as Position-Specific Scoring Matrix (PSSM) descriptor which contains information of biological evolutionary and the drug molecules are encoded as fingerprint feature vector which represents the existence of certain functional groups or fragments. Four benchmark datasets involving enzymes, ion channels, GPCRs and nuclear receptors, are independently used for establishing predictive models with Rotation Forest (RF) model. The proposed method achieved the prediction accuracy of 91.3%, 89.1%, 84.1% and 71.1% for four datasets respectively. In order to make our method more persuasive, we compared our classifier with the state-of-the-art Support Vector Machine (SVM) classifier. We also compared the proposed method with other excellent methods. Experimental results demonstrate that the proposed method is effective in the prediction of DTI, and can provide assistance for new drug research and development.

  11. In silico re-identification of properties of drug target proteins.

    PubMed

    Kim, Baeksoo; Jo, Jihoon; Han, Jonghyun; Park, Chungoo; Lee, Hyunju

    2017-05-31

    Computational approaches in the identification of drug targets are expected to reduce time and effort in drug development. Advances in genomics and proteomics provide the opportunity to uncover properties of druggable genomes. Although several studies have been conducted for distinguishing drug targets from non-drug targets, they mainly focus on the sequences and functional roles of proteins. Many other properties of proteins have not been fully investigated. Using the DrugBank (version 3.0) database containing nearly 6,816 drug entries including 760 FDA-approved drugs and 1822 of their targets and human UniProt/Swiss-Prot databases, we defined 1578 non-redundant drug target and 17,575 non-drug target proteins. To select these non-redundant protein datasets, we built four datasets (A, B, C, and D) by considering clustering of paralogous proteins. We first reassessed the widely used properties of drug target proteins. We confirmed and extended that drug target proteins (1) are likely to have more hydrophobic, less polar, less PEST sequences, and more signal peptide sequences higher and (2) are more involved in enzyme catalysis, oxidation and reduction in cellular respiration, and operational genes. In this study, we proposed new properties (essentiality, expression pattern, PTMs, and solvent accessibility) for effectively identifying drug target proteins. We found that (1) drug targetability and protein essentiality are decoupled, (2) druggability of proteins has high expression level and tissue specificity, and (3) functional post-translational modification residues are enriched in drug target proteins. In addition, to predict the drug targetability of proteins, we exploited two machine learning methods (Support Vector Machine and Random Forest). When we predicted drug targets by combining previously known protein properties and proposed new properties, an F-score of 0.8307 was obtained. When the newly proposed properties are integrated, the prediction performance

  12. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  13. Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

    PubMed Central

    Gordon, Laurie J.; Wayne, Gareth J.; Almqvist, Helena; Axelsson, Hanna; Seashore-Ludlow, Brinton; Treyer, Andrea; Lundbäck, Thomas; West, Andy; Hann, Michael M.; Artursson, Per

    2017-01-01

    Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. Fic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery. PMID:28701380

  14. Olopatadine: a drug for allergic conjunctivitis targeting the mast cell.

    PubMed

    Leonardi, Andrea; Quintieri, Luigi

    2010-04-01

    Ocular allergic diseases are characterized by specific activation of conjunctival mast cells with subsequent release of preformed and newly formed mediators. Mast cells are thus the first therapeutic target of ocular anti-allergic treatments. In this review, a Medline literature search was conducted on conjunctival mast cells, their role in ocular allergy and mast cell stabilization by ocular anti-allergic compounds. Olopatadine hydrochloride, a mast cell stabilizer and histamine receptor antagonist, has been shown to inhibit mast cell activation in an in vitro model of human mast cell culture, reducing histamine and TNF-alpha release and upregulating proinflammatory mediators in conjunctival epithelial cells. In the in vivo conjunctival allergen challenge (CAC) model in allergic subjects, combined with objective evaluations of tear mediators and cytology, olopatadine reduced histamine tear levels and all aspects of allergic inflammation, confirming the positive clinical effects observed in active allergic patients. Mast cells play a central role in the pathogenesis of ocular allergy. The CAC model is ideal for assessing the mast cell stabilizing effects of anti-allergic compounds. This review of clinical studies demonstrates the superiority of olopatadine compared with other topical allergic drugs.

  15. Geranylgeranyltransferase I as a target for anti-cancer drugs

    PubMed Central

    Philips, Mark R.; Cox, Adrienne D.

    2007-01-01

    Posttranslational modification is critical for the function of the gene products of ras oncogenes, which are frequently mutated in cancer. Ras proteins are modified by farnesyltransferase (FTase), but many related small GTPases that also end in a CAAX motif (where C is cysteine, A is often an aliphatic amino acid, and X is any amino acid) are modified by a closely related enzyme known as geranylgeranyltransferase type I (GGTase-I). Accordingly, inhibitors for both of these enzymes have been developed, and those active against FTase are in clinical trials. In this issue of the JCI, Sjogren et al. report the development of a mouse strain homozygous for a conditional allele of the gene that encodes GGTase-I (see the related article beginning on page 1294). They found that ablation of the GGTase-I–encoding gene in cells destined to produce lung tumors driven by oncogenic K-Ras resulted in delayed onset and decreased severity of disease, validating in a genetic model the theory that GGTase-I is a good target for anti-cancer drug development. PMID:17476354

  16. Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target.

    PubMed

    Supuran, Claudiu T; Capasso, Clemente

    2017-07-15

    Periodontitis originates from a microbial synergy causing the development of a mouth microbial imbalance (dysbiosis), consisting of a microbial community composed of anaerobic bacteria. Most studies concerning the treatment of periodontitis have primarily take into account the Gram-negative bacterium Porphyromonas gingivalis, because it is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium. Here, we focus our attention on the study of the carbonic anhydrases (CAs, EC 4.2.1.1) encoded in the genome of this pathogen as a possible drug target. Carbonic anhydrases are a superfamily of metalloenzymes, which catalyze the simple but physiologically crucial reaction of carbon dioxide hydration to bicarbonate and protons. Bacterial CAs have attracted significant attention for affecting the survival, invasion, and pathogenicity of many microorganisms. The P. gingivalis genome encodes for two CAs belonging to β-CA (PgiCAβ) and γ-CA (PgiCAγ) families. These two enzymes were cloned, heterologously expressed in Escherichia coli, and purified to homogeneity. Moreover, they were subject to extensive inhibition studies using the classical CA inhibitors (sulfonamides and anions) with the aim of identifying selective inhibitors of PgiCAβ and PgiCAγ to be used as pharmacological tools for P. gingivalis eradication.

  17. Targeted lipid based drug conjugates: a novel strategy for drug delivery.

    PubMed

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K; Pal, Dhananjay; Mitra, Ashim K

    2012-09-15

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in

  18. TARGETED LIPID BASED DRUG CONJUGATES: A NOVEL STRATEGY FOR DRUG DELIVERY

    PubMed Central

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K.; Pal, Dhananjay; Mitra, Ashim K.

    2012-01-01

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically towards cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [3H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs towards SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 µM) and B-12HS-ACV (23.99 ± 3.20 µM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 µM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [3H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [3H] biotin permeability in the

  19. Drug delivery and drug targeting with parenteral lipid nanoemulsions - A review.

    PubMed

    Hörmann, Karl; Zimmer, Andreas

    2016-02-10

    Lipid nanosized emulsions or nanoemulsions (NE) are oil in water dispersions with an oil droplet size of about 200nm. This size of oil droplets dispersed in a continuous water phase is a prerequisite for the parenteral, namely intravenous administration. Many parenteral nutrition and drug emulsions on the market confirm the safe use of NE over years. Parenteral emulsions loaded with APIs (active pharmaceutical ingredients) are considered as drug delivery systems (DDS). DDS focuses on the regulation of the in vivo dynamics, such as absorption, distribution, metabolism, and extended bioavailability, thereby improving the effectiveness and the safety of the drugs. Using an emulsion as a DDS, or through the use of surface diversification of the dispersed oil droplets of emulsions, a targeted increase of the API concentration in some parts of the human body can be achieved. This review focuses on NE similar to the marketed once with no or only low amount of additional surfactants beside the emulsifier from a manufacturing point of view (technique, used raw materials).

  20. tcTKB: an integrated cardiovascular toxicity knowledge base for targeted cancer drugs

    PubMed Central

    Xu, Rong; Wang, QuanQiu

    2015-01-01

    Targeted cancer drugs are often associated with unexpectedly high cardiovascular (CV) adverse events. Systematic approaches to studying CV events associated with targeted anticancer drugs have high potential for elucidating the complex pathways underlying targeted anti-cancer drugs. In this study, we built tcTKB, a comprehensive CV toxicity knowledge base for targeted cancer drugs, by extracting drug-CV pairs from five large-scale and complementary data sources. The data sources include FDA drug labels (44,979 labels), the FDA Adverse Event Reporting System (FAERS) (4,285,097 records), the Canada Vigilance Adverse Reaction Online Database (CVAROD) (1,107,752 records), published biomedical literature (21,354,075 records), and published full-text articles from the Journal of Oncology (JCO) (13,855 articles). tcTKB contains 14,351 drug-CV pairs for 45 targeted anticancer drugs and 1,842 CV events. We demonstrate that CV events positively correlate with drug target genes and drug metabolism genes, demonstrating that tcTKB in combination with other data resources, could facilitate our understanding of targeted anticancer drugs and their associated CV toxicities. PMID:26958275

  1. Drug-target interaction prediction: databases, web servers and computational models.

    PubMed

    Chen, Xing; Yan, Chenggang Clarence; Zhang, Xiaotian; Zhang, Xu; Dai, Feng; Yin, Jian; Zhang, Yongdong

    2016-07-01

    Identification of drug-target interactions is an important process in drug discovery. Although high-throughput screening and other biological assays are becoming available, experimental methods for drug-target interaction identification remain to be extremely costly, time-consuming and challenging even nowadays. Therefore, various computational models have been developed to predict potential drug-target associations on a large scale. In this review, databases and web servers involved in drug-target identification and drug discovery are summarized. In addition, we mainly introduced some state-of-the-art computational models for drug-target interactions prediction, including network-based method, machine learning-based method and so on. Specially, for the machine learning-based method, much attention was paid to supervised and semi-supervised models, which have essential difference in the adoption of negative samples. Although significant improvements for drug-target interaction prediction have been obtained by many effective computational models, both network-based and machine learning-based methods have their disadvantages, respectively. Furthermore, we discuss the future directions of the network-based drug discovery and network approach for personalized drug discovery based on personalized medicine, genome sequencing, tumor clone-based network and cancer hallmark-based network. Finally, we discussed the new evaluation validation framework and the formulation of drug-target interactions prediction problem by more realistic regression formulation based on quantitative bioactivity data. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  2. Drug Target Mining and Analysis of the Chinese Tree Shrew for Pharmacological Testing

    PubMed Central

    Liu, Jie; Lee, Wen-hui; Zhang, Yun

    2014-01-01

    The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research. PMID:25105297

  3. iDrug-Target: predicting the interactions between drug compounds and target proteins in cellular networking via benchmark dataset optimization approach.

    PubMed

    Xiao, Xuan; Min, Jian-Liang; Lin, Wei-Zhong; Liu, Zi; Cheng, Xiang; Chou, Kuo-Chen

    2015-01-01

    Information about the interactions of drug compounds with proteins in cellular networking is very important for drug development. Unfortunately, all the existing predictors for identifying drug-protein interactions were trained by a skewed benchmark data-set where the number of non-interactive drug-protein pairs is overwhelmingly larger than that of the interactive ones. Using this kind of highly unbalanced benchmark data-set to train predictors would lead to the outcome that many interactive drug-protein pairs might be mispredicted as non-interactive. Since the minority interactive pairs often contain the most important information for drug design, it is necessary to minimize this kind of misprediction. In this study, we adopted the neighborhood cleaning rule and synthetic minority over-sampling technique to treat the skewed benchmark datasets and balance the positive and negative subsets. The new benchmark datasets thus obtained are called the optimized benchmark datasets, based on which a new predictor called iDrug-Target was developed that contains four sub-predictors: iDrug-GPCR, iDrug-Chl, iDrug-Ezy, and iDrug-NR, specialized for identifying the interactions of drug compounds with GPCRs (G-protein-coupled receptors), ion channels, enzymes, and NR (nuclear receptors), respectively. Rigorous cross-validations on a set of experiment-confirmed datasets have indicated that these new predictors remarkably outperformed the existing ones for the same purpose. To maximize users' convenience, a public accessible Web server for iDrug-Target has been established at http://www.jci-bioinfo.cn/iDrug-Target/ , by which users can easily get their desired results. It has not escaped our notice that the aforementioned strategy can be widely used in many other areas as well.

  4. Thiamin (Vitamin B1) Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

    PubMed Central

    Du, Qinglin; Wang, Honghai; Xie, Jianping

    2011-01-01

    Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics. PMID:21234302

  5. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs

    PubMed Central

    de Souza, Wanderley; Rodrigues, Juliany Cola Fernandes

    2009-01-01

    Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14α-demethylase, and (f) azasterols, which inhibit Δ24(25)-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in

  6. Targeted Drug Delivery Systems and its Therapeutic Applications in Cancer and related Immune Pathological Conditions.

    PubMed

    Afridi, Saifullah; Iqbal, Jamshed; Anwar, Fareeha

    2017-06-05

    Earlier a century ago, Paul Ehrlich proposed an idea of a drug "magic bullet" that selectively eradicate diseased cells without harming the surrounding normal cells. Since a lot of progress has been attained in this field to discover new horizons for targeted delivery of drug. As major problem in disease therapy is the severe toxic effects of prescribed drugs on healthy cells. In order to reduce the adverse effects of chemotherapy on healthy tissues, herein, we summaries the use of recent drug delivery systems for targeted therapy. The selective delivery of the drugs to specific diseased cells or tissues is the dream of near future. Ideally, for target drug delivery systems, the system should be made up of a carriers and drugs, were carriers play the role of target delivery of the desired drug. This issue covers the recent advancement, in modern techniques for targeted drug delivery systems. It encompasses advances, benefits and limitations in state of art work of targeted drug delivery through hydrogels, microfluidics, nano particles, carbon nanotubes, polymeric micelles, liposomes, lipoprotein based drug carriers and dendrites. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Drug-target residence time--a case for G protein-coupled receptors.

    PubMed

    Guo, Dong; Hillger, Julia M; IJzerman, Adriaan P; Heitman, Laura H

    2014-07-01

    A vast number of marketed drugs act on G protein-coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug-target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on-target side effects. Hence, the compounds' kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo. We therefore propose that drug-target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug-target RT. © 2014 Wiley Periodicals, Inc.

  8. AMPA receptor regulation mechanisms: future target for safer neuroprotective drugs.

    PubMed

    Jayakar, Selwyn S; Dikshit, Madhu

    2004-06-01

    transporters, which require high-frequency firing for activation. On activation they might enhance the activity of NMDA receptors at the synapse to increase the levels of AMPA receptors. AMPA receptors surfaced at this juncture can contribute to heavy Ca2+ influx. Thus, blocking this pathway could be of considerable importance in preventing the excitotoxicity. A number of proteins such as the GRIP, PICK, and NSF also modulate the functions of AMPA receptors. Polyamines also block Ca2+ permeable AMPA receptors and thus are protective. NO and cGMP also play an important role in negatively regulating AMPA receptors and thus could offer protection. Modulation of AMPA receptor by different mechanisms has been discussed in the present review to implicate importance of these targets/pathways for safer and future neuroprotective drugs.

  9. Network based elucidation of drug response: from modulators to targets

    PubMed Central

    2013-01-01

    Network-based drug discovery aims at harnessing the power of networks to investigate the mechanism of action of existing drugs, or new molecules, in order to identify innovative therapeutic treatments. In this review, we describe some of the most recent advances in the field of network pharmacology, starting with approaches relying on computational models of transcriptional networks, then moving to protein and signaling network models and concluding with “drug networks”. These networks are derived from different sources of experimental data, or literature-based analysis, and provide a complementary view of drug mode of action. Molecular and drug networks are powerful integrated computational and experimental approaches that will likely speed up and improve the drug discovery process, once fully integrated into the academic and industrial drug discovery pipeline. PMID:24330611

  10. Structural systems pharmacology: a new frontier in discovering novel drug targets.

    PubMed

    Tan, Hepan; Ge, Xiaoxia; Xie, Lei

    2013-08-01

    The modern target-based drug discovery process, characterized by the one-drug-one-gene paradigm, has been of limited success. In contrast, phenotype-based screening produces thousands of active compounds but gives no hint as to what their molecular targets are or which ones merit further research. This presents a question: What is a suitable target for an efficient and safe drug? In this paper, we argue that target selection should take into account the proteome-wide energetic and kinetic landscape of drug-target interactions, as well as their cellular and organismal consequences. We propose a new paradigm of structural systems pharmacology to deconvolute the molecular targets of successful drugs as well as to identify druggable targets and their drug-like binders. Here we face two major challenges in structural systems pharmacology: How do we characterize and analyze the structural and energetic origins of drug-target interactions on a proteome scale? How do we correlate the dynamic molecular interactions to their in vivo activity? We will review recent advances in developing new computational tools for biophysics, bioinformatics, chemoinformatics, and systems biology related to the identification of genome-wide target profiles. We believe that the integration of these tools will realize structural systems pharmacology, enabling us to both efficiently develop effective therapeutics for complex diseases and combat drug resistance.

  11. Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets

    PubMed Central

    Duckworth, Benjamin P.; Nelson, Kathryn M.; Aldrich, Courtney C.

    2013-01-01

    Adenylation or adenylate-forming enzymes (AEs) are widely found in nature and are responsible for the activation of carboxylic acids to intermediate acyladenylates, which are mixed anhydrides of AMP. In a second reaction, AEs catalyze the transfer of the acyl group of the acyladenylate onto a nucleophilic amino, alcohol, or thiol group of an acceptor molecule leading to amide, ester, and thioester products, respectively. Mycobacterium tuberculosis encodes for more than 60 adenylating enzymes, many of which represent potential drug targets due to their confirmed essentiality or requirement for virulence. Several strategies have been used to develop potent and selective AE inhibitors including high-throughput screening, fragment-based screening, and the rationale design of bisubstrate inhibitors that mimic the acyladenylate. In this review, a comprehensive analysis of the mycobacterial adenylating enzymes will be presented with a focus on the identification of small molecule inhibitors. Specifically, this review will cover the aminoacyl tRNA-synthetases (aaRSs), MenE required for menaquinone synthesis, the FadD family of enzymes including the fatty acyl-AMP ligases (FAAL) and the fatty acyl-CoA ligases (FACLs) involved in lipid metabolism, and the nonribosomal peptide synthetase adenylation enzyme MbtA that is necessary for mycobactin synthesis. Additionally, the enzymes NadE, GuaA, PanC, and MshC involved in the respective synthesis of NAD, guanine, pantothenate, and mycothiol will be discussed as well as BirA that is responsible for biotinylation of the acyl CoA-carboxylases. PMID:22283817

  12. Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

    PubMed Central

    Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

    2014-01-01

    The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals. PMID:25140792

  13. Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

    PubMed

    Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

  14. Drug hypersensitivity reactions targeting the skin in dogs and cats.

    PubMed

    Voie, K L; Campbell, K L; Lavergne, S N

    2012-01-01

    Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.

  15. Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

    PubMed

    Abdolmaleki, Azizeh; Ghasemi, Jahan B; Ghasemi, Fatemeh

    2017-01-01

    Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. A stabilized peptide ligand for multifunctional glioma targeted drug delivery.

    PubMed

    Ying, Man; Shen, Qing; Zhan, Changyou; Wei, Xiaoli; Gao, Jie; Xie, Cao; Yao, Bingxin; Lu, Weiyue

    2016-12-10

    Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of (L)A7R to receptors. It is very interesting that cA7R adopting a different structure from (L)A7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or (L)A7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or (L)A7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to (L)A7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did (L

  17. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

    PubMed Central

    Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

    2016-01-01

    Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

  18. Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

    PubMed Central

    Weber, Wolfgang A; Czernin, Johannes; Phelps, Michael E; Herschman, Harvey R

    2010-01-01

    SUMMARY Targeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the ‘correct’, biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response. PMID:18097456

  19. Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.

    PubMed

    Haruki, Hirohito; Pedersen, Miriam Grønlund; Gorska, Katarzyna Irena; Pojer, Florence; Johnsson, Kai

    2013-05-24

    The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.

  20. Novel Drugs that Target ErbB2

    DTIC Science & Technology

    2012-05-01

    drugs including curcumin , arsenic trioxide, non-steroidal anti-inflammatory drugs, and triterpenoids such as celastrol, 2-cyano-1,12-dioxooleana-1,9...and tumors. These include curcumin , arsenic trioxide, tolfenamic acid and structurally related nonsteroidal anti-inflammatory drugs, BA, and...Jutooru I, Chintharlapalli S, Papineni S, Smith R, 3rd, Li X, et al. Curcumin decreases specificity protein expression in bladder cancer cells

  1. Dendritic polymer-based nanodevices for targeted drug delivery applications

    NASA Astrophysics Data System (ADS)

    Kannan, R. M.; Kolhe, Parag; Gurdag, Sezen; Khandare, Jayant; Lieh-Lai, Mary

    2004-03-01

    Dendrimers and hyperbranched polymers are unimolecular micellar nanostructures, characterized by globular shape ( ˜ 20 nm) and large density of functional groups at periphery. The tailorable end groups make them ideal for conjugation with drugs, ligands, and imagining agents, making them an attractive molecular nanodevices for drug delivery. Compared to linear polymers and nanoparticles, these nanodevices enter cells rapidly, carrying drugs and delivering them inside cells. Performance of nanodevices prepared for asthma and cancer drug delivery will be discussed. Our conjugation procedure produced very high drug payloads. Dendritic polymer-drug conjugates were very effective in transporting methotrexate (a chemotherapy drug) into both sensitive (CCRF-CEM cell line) and resistant cell line (CEM-MTX). The conjugate nanodevice was 3 times more effective than free drug in the sensitive line, and 9 times more effective in the resistant cell line (based on IC50). The physics of cell entry and drug release from these nanodevices are being investigated. The conjugates appear to enter cells through endocytosis, with the rate of entry dependent on end-group, molecular weight, the pH of the medium, and the cancerous nature of the cells.

  2. Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery.

    PubMed

    Chen, Rui; Xu, Liu; Fan, Qin; Li, Man; Wang, Jingjing; Wu, Li; Li, Weidong; Duan, Jinao; Chen, Zhipeng

    2017-11-01

    Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

  3. Multi-targeted hybrids based on HDAC inhibitors for anti-cancer drug discovery.

    PubMed

    Seo, Seung-Yong

    2012-02-01

    Multi-targeted hybrids combine two drugs in a single molecule to have greater medicinal effects than its individual components. Recently, a number of anti-cancer drug candidates such as CUDC-101 (Curis) have been designed based on linking properly two selected pharmacophores endowed with activity against different therapeutic targets.

  4. Human Progesterone A-Form as a Target for New Drug Discovery in Human Breast Cancer

    DTIC Science & Technology

    2001-07-01

    Progesterone A-Form as a Target for New Drug Discovery in Human Breast Cancer PRINCIPAL INVESTIGATOR: James Voltz Paloma Giangrande Donald McDonnell, Ph.D...SUBTITLE 5. FUNDING NUMBERS Human Progesterone A-Form as a Target for New Drug DAMD17-98-1-8070 Discovery in Human Breast Cancer 6. AUTHOR(S) James

  5. New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

    DTIC Science & Technology

    2014-07-01

    AD_________________ Award Number: W81XWH-11-1-0357 TITLE: New Treatments for Drug-Resistant Epilepsy that Target Presynaptic...14 Apr 2014 4. TITLE AND SUBTITLE New Treatments for Drug-Resistant Epilepsy that Target Presynaptic 5a. CONTRACT NUMBER Transmitter...temporal lobe epilepsy , and highlight the need for preventing the downregulation of sensitivity to levetiracetam observed with chronic administration

  6. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition

    PubMed Central

    Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A.; Feng, Dan; Bielecki, Timothy A.; Band, Vimla; Cohen, Samuel M.; Bronich, Tatiana K.; Band, Hamid

    2016-01-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla®; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance

  7. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    PubMed

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  8. The exploration of network motifs as potential drug targets from post-translational regulatory networks.

    PubMed

    Zhang, Xiao-Dong; Song, Jiangning; Bork, Peer; Zhao, Xing-Ming

    2016-02-08

    Phosphorylation and proteolysis are among the most common post-translational modifications (PTMs), and play critical roles in various biological processes. More recent discoveries imply that the crosstalks between these two PTMs are involved in many diseases. In this work, we construct a post-translational regulatory network (PTRN) consists of phosphorylation and proteolysis processes, which enables us to investigate the regulatory interplays between these two PTMs. With the PTRN, we identify some functional network motifs that are significantly enriched with drug targets, some of which are further found to contain multiple proteins targeted by combinatorial drugs. These findings imply that the network motifs may be used to predict targets when designing new drugs. Inspired by this, we propose a novel computational approach called NetTar for predicting drug targets using the identified network motifs. Benchmarking results on real data indicate that our approach can be used for accurate prediction of novel proteins targeted by known drugs.

  9. Advancing cancer drug discovery towards more agile development of targeted combination therapies.

    PubMed

    Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

    2012-01-01

    Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

  10. Genetic and proteomic approaches to identify cancer drug targets

    PubMed Central

    Roti, G; Stegmaier, K

    2012-01-01

    While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification. PMID:22166799

  11. The application of antitumor drug-targeting models on liver cancer.

    PubMed

    Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

    2016-06-01

    Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

  12. [Metabotropic glutamate receptors as targets for new drug development].

    PubMed

    Arkhipov, V I; Kapralova, M V

    2011-01-01

    The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.

  13. Dextran-gated, multifunctional mesoporous nanoparticle for glucose-responsive and targeted drug delivery.

    PubMed

    Sinha, Arjyabaran; Chakraborty, Atanu; Jana, Nikhil R

    2014-12-24

    Design of drug delivery nanocarrier having targeted recognition followed by bioresponsive controlled release, especially via glucose-responsive release, is a challenging issue. Here, we report magnetic mesoporous silica (MMS)-based drug delivery nanocarrier that can target specific cell and release drug via glucose-responsive gate. The design involves synthesis of MMS functionalized with phenylboronic acid and folate. After drug loading inside the pores of MMS, outside of the pores are closed by dextran via binding with phenylboronic acid. Dextran-gated pores are opened for drug release in the presence of glucose that competes binding with phenylboronic acid. We found that tolbutamide and camptothecin loaded MMS can target beta cells and cancer cells, respectively, release drugs depending on bulk glucose concentration and offers glucose concentration dependent cytotoxicity. Developed functional MMS can be used for advanced drug delivery applications for diabetes and cancers with more efficient therapy.

  14. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

    NASA Astrophysics Data System (ADS)

    Nawroth, T.; Johnson, R.; Krebs, L.; Khoshakhlagh, P.; Langguth, P.; Hellmann, N.; Goerigk, G.; Boesecke, P.; Bravin, A.; Le Duc, G.; Szekely, N.; Schweins, R.

    2016-09-01

    T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation.

  15. How specific are "target-specific" drugs? Celecoxib as a case in point.

    PubMed

    Sadée, Wolfgang; Bohn, Laura

    2006-08-01

    With the push to develop the next blockbuster drugs, continued surveillance of current bestsellers may not be given the full attention due. Upon wide-spread use, unexpected adverse effects begin to emerge. Although touted as highly specific, many of the newly developed drugs are likely to have secondary molecular targets-a potential cause of adverse effects. A molecular pharmacology approach that screens for multiple drug targets may shed light on the mechanisms that underlie both desired and adverse side-effects.

  16. A survey of yeast genomic assays for drug and target discovery

    PubMed Central

    Smith, Andrew M.; Ammar, Ron; Nislow, Corey; Giaever, Guri

    2010-01-01

    Over the past decade, the development and application of chemical genomic assays using the model organism Saccharomyces cerevisiae has provided powerful methods to identify the mechanism of action of known drugs and novel small molecules in vivo. These assays identify drug target candidates, genes involved in buffering drug target pathways and also help to define the general cellular response to small molecules. In this review, we examine current yeast chemical genomic assays and summarize the potential applications of each approach. PMID:20546776

  17. Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0114 TITLE: Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors PRINCIPAL INVESTIGATOR...14 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER NF140089 Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors 5b...to determine what factors limit delivery of drugs to tumors of the peripheral nerves, namely neurofibromas (NFs) and their derivative, the malignant

  18. Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

    DTIC Science & Technology

    2014-02-01

    Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy” 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0167 5c... Nanotechnologies in Living Systems”, Moscow Region, Russia, September, 2011. 3. “Ionic nanogels for drug delivery in cancer ”. NanoDDS’12; Atlantic City, New...AD Award Number: W81XWH-11-1-0167 TITLE: Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast

  19. Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

    DTIC Science & Technology

    2014-02-01

    Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy” 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0166 5c... Nanotechnologies in Living Systems”, Moscow Region, Russia, September, 2011. 3. “Ionic nanogels for drug delivery in cancer ”. NanoDDS’12; Atlantic City, New...AD Award Number: W81XWH-11-1-0166 TITLE: Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast

  20. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing.

    PubMed

    Oprea, Tudor I; Nielsen, Sonny Kim; Ursu, Oleg; Yang, Jeremy J; Taboureau, Olivier; Mathias, Stephen L; Kouskoumvekaki, Lrene; Sklar, Larry A; Bologa, Cristian G

    2011-03-14

    Finding new uses for old drugs is a strategy embraced by the pharmaceutical industry, with increasing participation from the academic sector. Drug repurposing efforts focus on identifying novel modes of action, but not in a systematic manner. With intensive data mining and curation, we aim to apply bio- and cheminformatics tools using the DRUGS database, containing 3,837 unique small molecules annotated on 1,750 proteins. These are likely to serve as drug targets and antitargets (i.e., associated with side effects, SE). The academic community, the pharmaceutical sector and clinicians alike could benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based on 7,684 approved drug labels, ADL (Dailymed) via text mining. From the ADL corresponding to 988 unique drugs, the "adverse reactions" section was mapped onto 174 SE, then clustered via principal component analysis into a 5x5 self-organizing map that was integrated into a Cytoscape network of SE-D-T-CO. This type of data can be used to streamline drug repurposing and may result in novel insights that can lead to the identification of novel drug actions.

  1. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing

    PubMed Central

    Oprea, Tudor I.; Nielsen, Sonny Kim; Ursu, Oleg; Yang, Jeremy J.; Taboureau, Olivier; Mathias, Stephen L.; Kouskoumvekaki, lrene; Sklar, Larry A.; Bologa, Cristian G.

    2012-01-01

    Finding new uses for old drugs is a strategy embraced by the pharmaceutical industry, with increasing participation from the academic sector. Drug repurposing efforts focus on identifying novel modes of action, but not in a systematic manner. With intensive data mining and curation, we aim to apply bio- and cheminformatics tools using the DRUGS database, containing 3,837 unique small molecules annotated on 1,750 proteins. These are likely to serve as drug targets and antitargets (i.e., associated with side effects, SE). The academic community, the pharmaceutical sector and clinicians alike could benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based on 7,684 approved drug labels, ADL (Dailymed) via text mining. From the ADL corresponding to 988 unique drugs, the “adverse reactions” section was mapped onto 174 SE, then clustered via principal component analysis into a 5x5 self-organizing map that was integrated into a Cytoscape network of SE-D-T-CO. This type of data can be used to streamline drug repurposing and may result in novel insights that can lead to the identification of novel drug actions. PMID:22287994

  2. Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles.

    PubMed

    Pan, Limin; He, Qianjun; Liu, Jianan; Chen, Yu; Ma, Ming; Zhang, Linlin; Shi, Jianlin

    2012-04-04

    Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diameter of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.

  3. Novel targeted bladder drug-delivery systems: a review

    PubMed Central

    Zacchè, Martino Maria; Srikrishna, Sushma; Cardozo, Linda

    2015-01-01

    The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs) have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD). Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin), nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy. PMID:26649286

  4. Novel targeted bladder drug-delivery systems: a review.

    PubMed

    Zacchè, Martino Maria; Srikrishna, Sushma; Cardozo, Linda

    2015-01-01

    The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs) have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD). Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin), nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy.

  5. Identification of drug candidates and repurposing opportunities through compound-target interaction networks.

    PubMed

    Cichonska, Anna; Rousu, Juho; Aittokallio, Tero

    2015-12-01

    System-wide identification of both on- and off-targets of chemical probes provides improved understanding of their therapeutic potential and possible adverse effects, thereby accelerating and de-risking drug discovery process. Given the high costs of experimental profiling of the complete target space of drug-like compounds, computational models offer systematic means for guiding these mapping efforts. These models suggest the most potent interactions for further experimental or pre-clinical evaluation both in cell line models and in patient-derived material. The authors focus here on network-based machine learning models and their use in the prediction of novel compound-target interactions both in target-based and phenotype-based drug discovery applications. While currently being used mainly in complementing the experimentally mapped compound-target networks for drug repurposing applications, such as extending the target space of already approved drugs, these network pharmacology approaches may also suggest completely unexpected and novel investigational probes for drug development. Although the studies reviewed here have already demonstrated that network-centric modeling approaches have the potential to identify candidate compounds and selective targets in disease networks, many challenges still remain. In particular, these challenges include how to incorporate the cellular context and genetic background into the disease networks to enable more stratified and selective target predictions, as well as how to make the prediction models more realistic for the practical drug discovery and therapeutic applications.

  6. [Multimorbidity and multi-target-therapy with herbal drugs].

    PubMed

    Saller, R; Rostock, M

    2012-12-12

    The active components of herbal drugs and substances are pleiotropic multi-ingredient compounds with multitarget properties including antiinflammatory effects. A pleiotropic inhibition of inflammation could play an important role in mutlimorbide patients as an attempt of prevention or retardation of metastasis. A large number of experimental data for European and non-European herbal drugs as well as various herbal drug combinations suggest such a possibility. Despite the so far small number of clinical studies, such an experimental herbal treatment could appear to be reasonable and acceptable, provided that there are data available on quality and safety of these herbal drugs by treatments of patients with various diseases. Besides, herbal drugs and substances play a growing role the treatment of patients with multimorbidity. Many of these herbal drugs have antiinflammatory effects beside their proved symptomatic efficacy in a lot of other diseases. The specific selection of herbal drugs that are efficacious in specific indications and additionally showed antiinflammatory effects offers the possibility of simultaneous antiinflammatory and specific efficacy. St. John's Wort and milk thistle belong to the oldest and to the best experimentally and clinically examined herbal remedies. The spectrum of internal and external uses of Hypercum perforatum as a multicompound herbal drug includes functional gastro-intestinal complaint and illness, skin disease, mucosal lesion, superficial injury, depressive upset and depression, somatoform disorders, restlessness, nervosity, convalescence, exhaustion and sleep disturbances respectively. The plurivalent character of the multicompound even enables a broad spectrum of activity. This might justify to prefer St. John's Wort to other drugs in a wide range of treatments: In multimorbide patients with depression or in depressive patients with coronary heart disease the anti-inflammatory effects could mean an additional advantage

  7. Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

    PubMed Central

    Kim, Eunhee G.; Kim, Kristine M.

    2015-01-01

    Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris® (anti-CD30-drug conjugate) and Kadcyla® (anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed. PMID:26535074

  8. Targeting receptors, transporters and site of absorption to improve oral drug delivery.

    PubMed

    Hamman, J H; Demana, P H; Olivier, E I

    2007-01-01

    Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.

  9. Targeting Receptors, Transporters and Site of Absorption to Improve Oral Drug Delivery

    PubMed Central

    Hamman, J.H.; Demana, P.H.; Olivier, E.I.

    2007-01-01

    Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place. PMID:21901064

  10. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

    DTIC Science & Technology

    2013-09-01

    degradable dendrimers and its applications for drug delivery .............................................. 23 3.1 Dendrimer design and synthesis...drug delivery .......................................................... 26 3.3 Dendrimer /lipid nanoassembly as “cluster bomb” for cascade tumor...degradable dendrimers and applied such dendrimers to formulate novel drug delivery systems to improve the limited penetration of anti-cancer drugs within

  11. For Some Skin Cancers, Targeted Drug Hits the Mark

    Cancer.gov

    Two studies reported June 7, 2012, in NEJM indicate that the drug vismodegib can elicit responses in people with advanced or metastatic basal cell carcinoma and help shrink or prevent tumors in those with basal cell nevus syndrome.

  12. Nanoparticles laden in situ gelling system for ocular drug targeting

    PubMed Central

    Kumar, Divya; Jain, Nidhi; Gulati, Neha; Nagaich, Upendra

    2013-01-01

    Designing an ophthalmic drug delivery system is one of the most difficult challenges for the researchers. The anatomy and physiology of eye create barriers like blinking which leads to the poor retention time and penetration of drug moiety. Some conventional ocular drug delivery systems show shortcomings such as enhanced pre-corneal elimination, high variability in efficiency, and blurred vision. To overcome these problems, several novel drug delivery systems such as liposomes, nanoparticles, hydrogels, and in situ gels have been developed. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion-induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. Thus, a combination of two drug delivery systems, i.e., nanoparticles and in situ gel, has been developed which is known as nanoparticle laden in situ gel. This review describes every aspects of this novel formulation, which present the readers an exhaustive detail and might contribute to research and development. PMID:23662277

  13. Nanoparticles laden in situ gelling system for ocular drug targeting.

    PubMed

    Kumar, Divya; Jain, Nidhi; Gulati, Neha; Nagaich, Upendra

    2013-01-01

    Designing an ophthalmic drug delivery system is one of the most difficult challenges for the researchers. The anatomy and physiology of eye create barriers like blinking which leads to the poor retention time and penetration of drug moiety. Some conventional ocular drug delivery systems show shortcomings such as enhanced pre-corneal elimination, high variability in efficiency, and blurred vision. To overcome these problems, several novel drug delivery systems such as liposomes, nanoparticles, hydrogels, and in situ gels have been developed. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion-induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. Thus, a combination of two drug delivery systems, i.e., nanoparticles and in situ gel, has been developed which is known as nanoparticle laden in situ gel. This review describes every aspects of this novel formulation, which present the readers an exhaustive detail and might contribute to research and development.

  14. Nanostructured lipid carriers and their current application in targeted drug delivery.

    PubMed

    Jaiswal, Piyush; Gidwani, Bina; Vyas, Amber

    2016-01-01

    In the last few decades, various drug-delivery technologies have emerged and a fascinating part of this has been the development of nanoscale drug delivery devices. Nanoparticles (NPs) and other colloidal drug-delivery systems modify the kinetics, drug distribution in the body and release profile of an associated drug. Nanostructured lipid carriers (NLCs) have been reported to be an alternative system to emulsions, liposomes, microparticles, solid lipid nanoparticles (SLNs) and their polymeric counterparts due to their numerous advantages. This paper basically reviews the types of NLCs, mechanism of skin penetration, stability related issues along with their production techniques, characterisation and applications towards targeted drug delivery.

  15. On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs.

    PubMed

    Wu, Chyuan-Chuan; Li, Yi-Ching; Wang, Ying-Ren; Li, Tsai-Kun; Chan, Nei-Li

    2013-12-01

    Type II topoisomerases (Top2s) alter DNA topology via the formation of an enzyme-DNA adduct termed cleavage complex, which harbors a transient double-strand break in one DNA to allow the passage of another. Agents targeting human Top2s are clinically active anticancer drugs whose trapping of Top2-mediated DNA breakage effectively induces genome fragmentation and cell death. To understand the structural basis of this drug action, we previously determined the structure of human Top2 β-isoform forming a cleavage complex with the drug etoposide and DNA, and described the insertion of drug into DNA cleavage site and drug-induced decoupling of catalytic groups. By developing a post-crystallization drug replacement procedure that simplifies structural characterization of drug-stabilized cleavage complexes, we have extended the analysis toward other structurally distinct drugs, m-AMSA and mitoxantrone. Besides the expected drug intercalation, a switch in ribose puckering in the 3'-nucleotide of the cleavage site was robustly observed in the new structures, representing a new mechanism for trapping the Top2 cleavage complex. Analysis of drug-binding modes and the conformational landscapes of the drug-binding pockets provide rationalization of the drugs' structural-activity relationships and explain why Top2 mutants exhibit differential effects toward each drug. Drug design guidelines were proposed to facilitate the development of isoform-specific Top2-targeting anticancer agents.

  16. Tumor Targeting of Polymeric Nanoparticles Conjugated with Peptides, Saccharides, and Small Molecules for Anticancer Drugs.

    PubMed

    Bayram, Banu; Özgür, Aykut; Tutar, Lütfi; Tutar, Yusuf

    2017-06-07

    Targeting drugs or pharmaceutical compounds to tumor site increases cancer treatment efficiency and therapeutic outcome. Nanoparticles are unique delivery systems for site-targeting within an organism. Many novel technologies have been established in drug research and development area. Nanotechnology now offers nanometer size polymeric nanoparticles and these particles direct drugs to their targets, protect drugs against degradation, and release the drug in a controlled manner. Modification of nanoparticle surface by molecules leads to prolonged retention and accumulation in the target area of the organism. Current efforts of designing polymeric nanoparticles include drug activation in the target area, controlled drug release at the site upon stimulation, and increased drug loading capacity of drug polymer conjugates. Recent progress in molecular mechanism elucidation of cancer cell and rising research in nanoparticle designs may provide efficient cancer treatment modality and innovative nanoparticle designs in the near future. Recent years have seen many developments in the field of innovative peptide based drug nanoparticles. Although none of them approved to be used in clinic yet, peptides are promising structures due to their simple and non-antigenic nature. Biodegrable materials are also preferred materials in drug delivery. Polysaccharide-based micelle systems improve hydrophobic drug and protein delivery. Ease of saccharide structure modification improves pharmacokinetic and pharmacodynamic properties of drug molecules as well as their delivery to a specific site in a controlled manner and sustained rate. Small molecules, especially drugs, conjugated to nanoparticles and several nanoparticles of this type are in the clinical trials and at the market. This review provides recent developments of polymeric nanoparticles conjugated with peptides, saccharides, and small molecules in cancer theraphy. Copyright© Bentham Science Publishers; For any queries, please

  17. Application of traditional Chinese medicine preparation in targeting drug delivery system.

    PubMed

    Xu, Wei; Xing, Feng J; Dong, Kai; You, Cuiyu; Yan, Yan; Zhang, Lu; Zhao, Guilan; Chen, Youliang; Wang, Ke

    2015-05-01

    Targeting drug system (TDS) or targeted drug delivery system (TDDS) is a new kind of drug delivery system which could make drug to be directly concentrated on the target site with high curative effects and low side-effects. As the quintessence of Chinese culture, traditional Chinese medicine (TCM) has a large advantage in many disease clinical treatments, especially in cancer, hypertension and many other intractable diseases owing to their low toxicity and side-effects relative to western medicine. This article reviews literatures on development of TCM-targeted preparations which were published in the past 10 years. TDS including active-targeting, passive-targeting and physical-chemical-targeting preparations were introduced through domestic and overseas literatures to reveal the unique advantages of TCM-targeting preparations in drug delivery system. In this article, we have reviewed some kinds of TCM-targeting preparations and indicated that great attention should be paid to the research on the TCM-targeting preparations.

  18. Some Remarks on Prediction of Drug-Target Interaction with Network Models.

    PubMed

    Zhang, Shao-Wu; Yan, Xiao-Ying

    2017-01-01

    System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict Drug-Target Interactions (DTI). In this review, we make a survey on the recent advances in predicting drug-target interaction with network-based models from the following aspects: i) Available public data sources and benchmark datasets; ii) Drug/target similarity metrics; iii) Network construction; iv) Common network algorithms; v) Performance comparison of existing network-based DTI predictors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

    PubMed Central

    Pan, Dipanjan; Pham, Christine TN; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

    2016-01-01

    Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies eq