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Sample records for cancer rational design

  1. Rationally designed nanovehicles to overcome cancer chemoresistance.

    PubMed

    Livney, Yoav D; Assaraf, Yehuda G

    2013-11-01

    Drug resistance is a primary hindrance towards curative cancer chemotherapy. Nanotechnology holds great promise in establishing efficacious and innovative strategies to overcome chemoresistance, and markedly facilitate complementary treatments and cancer diagnostics. Various nanomedical devices are being introduced and evaluated, demonstrating encouraging results. While stealth liposomes serve as a benchmark, astonishing progress is witnessed in polymeric nanovehicles, sometimes combined with low molecular weight surfactants, some of which inhibit drug resistance in addition to solubilizing drugs. Cutting edge multifunctional or quadrugnostic nanoparticles currently developed offer simultaneous targeted delivery of chemotherapeutics and chemosensitizers or drug-resistance gene silencing cargo, along with diagnostic imaging agents, like metallic NPs. Viral and cellular components offer exciting new routes for cancer targeting and treatment. Targeting intracellular compartments is another challenging frontier spawning pioneering approaches and results. To further enhance rational design of nanomedicine for overcoming drug resistance, we review the latest thoughts and accomplishments in recent literature. PMID:23954781

  2. Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules

    PubMed Central

    Hedvat, Michael; Emdad, Luni; Das, Swadesh K.; Kim, Keetae; Dasgupta, Santanu; Thomas, Shibu; Hu, Bin; Zhu, Shan; Dash, Rupesh; Quinn, Bridget A.; Oyesanya, Regina A.; Kegelman, Timothy P.; Sokhi, Upneet K.; Sarkar, Siddik; Erdogan, Eda; Menezes, Mitchell E.; Bhoopathi, Praveen; Wang, Xiang-Yang; Pomper, Martin G.; Wei, Jun; Wu, Bainan; Stebbins, John L.; Diaz, Paul W.; Reed, John C.; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

    2013-01-01

    Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specific-promoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy. PMID:22931411

  3. Rational Design of Multi-Stimuli-Responsive Nanoparticles for Precise Cancer Therapy.

    PubMed

    An, Xiaonan; Zhu, Aijun; Luo, Huanhuan; Ke, Hengte; Chen, Huabing; Zhao, Youliang

    2016-06-28

    Stimuli-responsive nanoparticles with target capacity are of great interest in drug delivery for cancer therapy. However, the challenge is to achieve highly smart release with precise spatiotemporal control for cancer therapy. Herein, we report the preparation and properties of multi-stimuli-responsive nanoparticles through the co-assembly of a 3-arm star quaterpolymer with a near-infrared (NIR) photothermal agent and chemotherapeutic compound. The nanoparticles can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photoinduced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Thus, this rational design of nanoparticles with multiple responsiveness represents a versatile strategy to provide smart drug delivery paradigms for cancer therapy. PMID:27285378

  4. Rationally designed treatment for metastatic colorectal cancer: Current drug development strategies

    PubMed Central

    Spiliopoulou, Pavlina; Arkenau, Hendrik-Tobias

    2014-01-01

    The therapeutic landscape of metastatic colorectal cancer (mCRC) has changed substantially with the emergence of new molecularly targeted agents (MTA) used as single agents or alongside standard chemotherapy. The use of these MTAs extended the overall survival of patients with mCRC to a level that current chemotherapeutics alone could not achieve. In addition, improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC and MTAs have been found to have a significant role here too, as they aid resectability. However, for the majority of patients, mCRC remains an invariably incurable disease necessitating continued courses of combined treatment modalities. During the course of these treatments, either cytotoxic or biological, cancer cells maintain their ability to acquire mitogenic mutations which render them resistant to treatment. Key challenges remain to identify appropriate subsets of patients who will most likely benefit from these new MTAs and effectively select these based on validated biomarkers. Moreover, better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments, so that we can maximise the survivorship of mCRC patients. This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies. PMID:25132745

  5. Rational design of cancer-targeted BSA protein nanoparticles as radiosensitizer to overcome cancer radioresistance.

    PubMed

    Huang, Yanyu; Luo, Yi; Zheng, Wenjie; Chen, Tianfeng

    2014-01-01

    Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy. PMID:25314331

  6. Cancer Drug Delivery: Considerations in the Rational Design of Nanosized Bioconjugates

    PubMed Central

    2015-01-01

    In order to efficiently deliver anticancer agents to tumors, biocompatible nanoparticles or bioconjugates, including antibody–drug conjugates (ADCs), have recently been designed, synthesized, and tested, some even in clinical trials. Controlled delivery can be enhanced by changing specific design characteristics of the bioconjugate such as its size, the nature of the payload, and the surface features. The delivery of macromolecular drugs to cancers largely relies on the leaky nature of the tumor vasculature compared with healthy vessels in normal organs. When administered intravenously, macromolecular bioconjugates and nanosized agents tend to circulate for prolonged times, unless they are small enough to be excreted by the kidney or stealthy enough to evade the macrophage phagocytic system (MPS), formerly the reticulo-endothelial system (RES). Therefore, macromolecular bioconjugates and nanosized agents with long circulation times leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, success of cancer drug delivery only relying on the EPR effect is still limited. To cure cancer patients, further improvement of drug delivery is required by both designing superior agents and enhancing EPR effects. In this Review, we describe the basis of macromolecular or nanosized bioconjugate delivery into cancer tissue and discuss current diagnostic methods for evaluating leakiness of the tumor vasculature. Then, we discuss methods to augment conventional “permeability and retention” effects for macromolecular or nanosized bioconjugates in cancer tissue. PMID:25385142

  7. Rational design for multifunctional non-liposomal lipid-based nanocarriers for cancer management: theory to practice

    PubMed Central

    2013-01-01

    Nanomedicines have gained more and more attention in cancer therapy thanks to their ability to enhance the tumour accumulation and the intracellular uptake of drugs while reducing their inactivation and toxicity. In parallel, nanocarriers have been successfully employed as diagnostic tools increasing imaging resolution holding great promises both in preclinical research and in clinical settings. Lipid-based nanocarriers are a class of biocompatible and biodegradable vehicles that provide advanced delivery of therapeutic and imaging agents, improving pharmacokinetic profile and safety. One of most promising engineering challenges is the design of innovative and versatile multifunctional targeted nanotechnologies for cancer treatment and diagnosis. This review aims to highlight rational approaches to design multifunctional non liposomal lipid-based nanocarriers providing an update of literature in this field. PMID:24564841

  8. Rational Design of Iron Oxide Nanoparticles as Targeted Nanomedicines for Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Kievit, Forrest M.

    2011-07-01

    Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables non-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. This dissertation is aimed at development of SPION-based nanomedicines to overcome the current limitations in cancer therapy. These limitations include non-specificity of therapy which can harm healthy tissue, the difficulty in delivering nucleic acids for gene therapy, the formation of drug resistance, and the inability to detect and treat micrometastases. First, a SPION-based non-viral gene delivery vehicle was developed through functionalization of the SPION core with a co-polymer designed to provide stable binding of DNA and low toxicity which showed excellent gene delivery in vitro and in vivo. This SPION-based non-viral gene delivery vehicle was then activated with a targeting agent to improve gene delivery throughout a xenograft tumor of brain cancer. It was found that targeting did not promote the accumulation of SPIONs at the tumor site, but rather improved the distribution of SPIONs throughout the tumor so a higher proportion of cells received treatment. Next, the high surface area of SPIONs was utilized for loading large amounts of drug which was shown to overcome the multidrug resistance acquired by many cancer cells. Drug bound to SPIONs showed significantly higher multidrug resistant cell uptake as compared to free drug which translated into improved cell kill. Also, an antibody activated SPION was developed and was shown to be able to target micrometastases in a transgenic animal model of metastatic breast cancer. These SPION-based nanomedicines

  9. Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer.

    PubMed

    Goldman, Aaron; Kulkarni, Ashish; Kohandel, Mohammad; Pandey, Prithvi; Rao, Poornima; Natarajan, Siva Kumar; Sabbisetti, Venkata; Sengupta, Shiladitya

    2016-06-28

    The development of resistance is the major cause of mortality in cancer. Combination chemotherapy is used clinically to reduce the probability of evolution of resistance. A similar trend toward the use of combinations of drugs is also emerging in the application of cancer nanomedicine. However, should a combination of two drugs be delivered from a single nanoparticle or should they be delivered in two different nanoparticles for maximal efficacy? We explored these questions in the context of adaptive resistance, which emerges as a phenotypic response of cancer cells to chemotherapy. We studied the phenotypic dynamics of breast cancer cells under cytotoxic chemotherapeutic stress and analyzed the data using a phenomenological mathematical model. We demonstrate that cancer cells can develop adaptive resistance by entering into a predetermined transitional trajectory that leads to phenocopies of inherently chemoresistant cancer cells. Disrupting this deterministic program requires a unique combination of inhibitors and cytotoxic agents. Using two such combinations, we demonstrate that a 2-in-1 nanomedicine can induce greater antitumor efficacy by ensuring that the origins of adaptive resistance are terminated by deterministic spatially constrained delivery of both drugs to the target cells. In contrast, a combination of free-form drugs or two nanoparticles, each carrying a single payload, is less effective, arising from a stochastic distribution to cells. These findings suggest that 2-in-1 nanomedicines could emerge as an important strategy for targeting adaptive resistance, resulting in increased antitumor efficacy. PMID:27257911

  10. Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Sun, Qihang

    Nanocarriers can minimize the side effects and improve therapeutic efficacy of anticancer drugs. Although some success has been achieved via active or passive drug delivery to tumor cells, the known nanocarriers are far from satisfying therapeutic efficacy expectations. This is because they usually fail in one of the four crucial requirements, that is, to retain drug in blood circulation but release it reliably in tumor cells and to be stealthy in transport in circulation and tumor tissue but sticky upon arrival at the tumor cell. Therefore, the goal of this work is to fabricate nanoassemblies of dendrimers and lipids to address all these challenges. Particularly, nanoassemblies designed and prepared in this work are illustrated to improve the tumor tissue penetration. Examples of dendrimers synthesized in this work are water-insoluble, pH-dependent water-insoluble and water-soluble biodegradable polyester dendrimers. These dendrimers are shown to be encapsulated by commonly used fusogenic and long-circulating lipids to form reliable nanoassemblies. The dendrimer/lipid nanocarriers are used to demonstrate a cascade drug delivery. They are expected to be stable in circulation, due to their appropriately large size, but to release the drug-loaded dendrimers in tumor tissue. The released dendrimers carrying drugs are much smaller and hence expected to have a much deeper penetration throughout the tumor tissue.

  11. Rational design of helical architectures

    PubMed Central

    Chakrabarti, Dwaipayan; Fejer, Szilard N.; Wales, David J.

    2009-01-01

    Nature has mastered the art of creating complex structures through self-assembly of simpler building blocks. Adapting such a bottom-up view provides a potential route to the fabrication of novel materials. However, this approach suffers from the lack of a sufficiently detailed understanding of the noncovalent forces that hold the self-assembled structures together. Here we demonstrate that nature can indeed guide us, as we explore routes to helicity with achiral building blocks driven by the interplay between two competing length scales for the interactions, as in DNA. By characterizing global minima for clusters, we illustrate several realizations of helical architecture, the simplest one involving ellipsoids of revolution as building blocks. In particular, we show that axially symmetric soft discoids can self-assemble into helical columnar arrangements. Understanding the molecular origin of such spatial organisation has important implications for the rational design of materials with useful optoelectronic applications.

  12. Rational design of a receptor-targeted photodynamic molecular beacon for the multilevel control of singlet oxygen production and PDT activity in cancer cells

    NASA Astrophysics Data System (ADS)

    Chen, Juan; Stefflova, Klara; Warren, Mike; Bu, Jiachuan; Wilson, Brian C.; Zheng, Gang

    2007-02-01

    Photodynamic therapy (PDT) involves the combined action of light, oxygen and a photosensitizer (PS). It offers unique control in the PS's action because the key cytotoxic agent, singlet oxygen (1O II), is only produced in situ upon irradiation. The 1O II production can be controlled in three levels. The first level involves the judicious use of fiber optics to selectively deliver light to disease tissues. The second level is to exert control over the PS's localization by selectively delivering PS to cancer cells. The third level is to exert control of the PS's ability to generate 1O II in responding to specific cancer biomarkers. Here, we present two PDT agents based on the latter two levels of 1O II control. The first PDT agent "PPF" contains a PS (Pyro) and a tumor homing molecule (folate) and a peptide linker. PPF was found to be selectively accumulated in cancer cells via folate receptor (FR) pathway. The second PDT agent "PP MMP7B" is a matrix metalloproteinase-7 (MMP7)-triggered photodynamic molecular beacon (PMB) containing a PS (Pyro), a 1O II quencher (BHQ3) and a MMP7-cleavable peptide linker. Thus, the 1O II production of PP MMP7B is highly sequence-specific and its photodynamic cytotoxicity is MMP7-dependent. Since these agents are designed to share functional modules (PS and peptide linker) and common cancer cell model (KB cells overexpress both FR and MMP7), it forms the basis for rational design of receptor-targeted PMB for achieving a multi-level control of 1O II production in cancer cells, which in term, could provide a much higher level of PDT selectivity.

  13. G4-DNA Formation in the HRAS Promoter and Rational Design of Decoy Oligonucleotides for Cancer Therapy

    PubMed Central

    Membrino, Alexandro; Cogoi, Susanna; Pedersen, Erik B.; Xodo, Luigi E.

    2011-01-01

    HRAS is a proto-oncogene involved in the tumorigenesis of urinary bladder cancer. In the HRAS promoter we identified two G-rich elements, hras-1 and hras-2, that fold, respectively, into an antiparallel and a parallel quadruplex (qhras-1, qhras-2). When we introduced in sequence hras-1 or hras-2 two point mutations that block quadruplex formation, transcription increased 5-fold, but when we stabilized the G-quadruplexes by guanidinium phthalocyanines, transcription decreased to 20% of control. By ChIP we found that sequence hras-1 is bound only by MAZ, while hras-2 is bound by MAZ and Sp1: two transcription factors recognizing guanine boxes. We also discovered by EMSA that recombinant MAZ-GST binds to both HRAS quadruplexes, while Sp1-GST only binds to qhras-1. The over-expression of MAZ and Sp1 synergistically activates HRAS transcription, while silencing each gene by RNAi results in a strong down-regulation of transcription. All these data indicate that the HRAS G-quadruplexes behave as transcription repressors. Finally, we designed decoy oligonucleotides mimicking the HRAS quadruplexes, bearing (R)-1-O-[4-(1-Pyrenylethynyl) phenylmethyl] glycerol and LNA modifications to increase their stability and nuclease resistance (G4-decoys). The G4-decoys repressed HRAS transcription and caused a strong antiproliferative effect, mediated by apoptosis, in T24 bladder cancer cells where HRAS is mutated. PMID:21931711

  14. Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety.

    PubMed

    Ferla, Salvatore; Bassetto, Marcella; Pertusati, Fabrizio; Kandil, Sahar; Westwell, Andrew D; Brancale, Andrea; McGuigan, Christopher

    2016-08-01

    Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified. PMID:27301368

  15. Preclinical Development of Novel Rac1-GEF Signaling Inhibitors using a Rational Design Approach in Highly Aggressive Breast Cancer Cell Lines

    PubMed Central

    Cardama, Georgina A; Comin, Maria J; Hornos, Leandro; Gonzalez, Nazareno; Defelipe, Lucas; Turjanski, Adrian G; Alonso, Daniel F; Gomez, Daniel E; Menna, Pablo Lorenzano

    2014-01-01

    Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy. PMID:24066799

  16. Rational Design of Improved Pharmabiotics

    PubMed Central

    Sleator, Roy D.; Hill, Colin

    2009-01-01

    Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications. PMID:19753318

  17. Rational design of improved pharmabiotics.

    PubMed

    Sleator, Roy D; Hill, Colin

    2009-01-01

    Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications. PMID:19753318

  18. Rational design of nanomaterials for water treatment

    NASA Astrophysics Data System (ADS)

    Li, Renyuan; Zhang, Lianbin; Wang, Peng

    2015-10-01

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits. It is now a popular perception that the solutions to the existing and future water challenges will hinge upon further developments in nanomaterial sciences. The concept of rational design emphasizes on `design-for-purpose' and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress in rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil-water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid to the chemical concepts related to nanomaterial design throughout the review.

  19. Rational design of nanomaterials for water treatment.

    PubMed

    Li, Renyuan; Zhang, Lianbin; Wang, Peng

    2015-11-01

    The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits. It is now a popular perception that the solutions to the existing and future water challenges will hinge upon further developments in nanomaterial sciences. The concept of rational design emphasizes on 'design-for-purpose' and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress in rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil-water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid to the chemical concepts related to nanomaterial design throughout the review. PMID:26437738

  20. Rationally designed substrates for SERS biosensing

    NASA Astrophysics Data System (ADS)

    Yan, Bo

    The large electromagnetic field enhancement provided by nanostructured noble metal surfaces forms the foundation for a series of enabling optical analytical techniques, such as surface enhanced Raman spectroscopy (SERS), surface enhanced IR absorption spectroscopy (SEIRA), surface enhanced fluorescent microscopy (SEF), to name only a few. Critical sensing applications have, however, other substrate requirements than mere peak signal enhancement. The substrate needs to be reliable, provide reproducible signal enhancements, and be amenable to a combination with microfluidic chips or other integrated sensor platforms. These needs motivate the development of engineerable SERS substrate "chips" with defined near- and far-field responses. In this dissertation, two types of rationally designed SERS substrates - nanoparticle cluster arrays (NCAs) and SERS stamp - will be introduced and characterized. NCAs were fabricated through a newly developed template guided self-assembly fabrication approach, in which chemically synthesized nanoparticles are integrated into predefined patterns using a hybrid top-down/bottom-up approach. Since this method relies on chemically defined building blocks, it can overcome the resolution limit of conventional lithographical methods and facilitates higher structural complexity. NCAs sustain near-field interactions within individual clusters as well as between entire neighboring clusters and create a multi-scale cascaded E-field enhancement throughout the entire array. SERS stamps were generated using an oblique angle metal deposition on a lithographically defined piston. When mounted on a nanopositioning stage, the SERS stamps were enabled to contact biological surfaces with pristine nanostructured metal surfaces for a label-free spectroscopic characterization. The developed engineered substrates were applied and tested in critical sensing applications, including the ultra-trace detection of explosive vapors, the rapid discrimination of

  1. Strategies in the rational drug design.

    PubMed

    Mavromoustakos, T; Durdagi, S; Koukoulitsa, C; Simcic, M; Papadopoulos, M G; Hodoscek, M; Grdadolnik, S Golic

    2011-01-01

    Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed. PMID:21568895

  2. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  3. Rational Experimental Design for Electrical Resistivity Imaging

    NASA Astrophysics Data System (ADS)

    Mitchell, V.; Pidlisecky, A.; Knight, R.

    2008-12-01

    Over the past several decades advances in the acquisition and processing of electrical resistivity data, through multi-channel acquisition systems and new inversion algorithms, have greatly increased the value of these data to near-surface environmental and hydrological problems. There has, however, been relatively little advancement in the design of actual surveys. Data acquisition still typically involves using a small number of traditional arrays (e.g. Wenner, Schlumberger) despite a demonstrated improvement in data quality from the use of non-standard arrays. While optimized experimental design has been widely studied in applied mathematics and the physical and biological sciences, it is rarely implemented for non-linear problems, such as electrical resistivity imaging (ERI). We focus specifically on using ERI in the field for monitoring changes in the subsurface electrical resistivity structure. For this application we seek an experimental design method that can be used in the field to modify the data acquisition scheme (spatial and temporal sampling) based on prior knowledge of the site and/or knowledge gained during the imaging experiment. Some recent studies have investigated optimized design of electrical resistivity surveys by linearizing the problem or with computationally-intensive search algorithms. We propose a method for rational experimental design based on the concept of informed imaging, the use of prior information regarding subsurface properties and processes to develop problem-specific data acquisition and inversion schemes. Specifically, we use realistic subsurface resistivity models to aid in choosing source configurations that maximize the information content of our data. Our approach is based on first assessing the current density within a region of interest, in order to provide sufficient energy to the region of interest to overcome a noise threshold, and then evaluating the direction of current vectors, in order to maximize the

  4. Rational Design of Biobetters with Enhanced Stability.

    PubMed

    Courtois, Fabienne; Schneider, Curtiss P; Agrawal, Neeraj J; Trout, Bernhardt L

    2015-08-01

    Biotherapeutics are the fastest growing class of pharmaceutical with a rapidly evolving market facing the rise of biosimilar and biobetter products. In contrast to a biosimilar, which is derived from the same gene sequence as the innovator product, a biobetter has enhanced properties, such as enhanced efficacy or reduced immunogenicity. Little work has been carried out so far to increase the intrinsic stability of biotherapeutics via sequence changes, even though, aggregation, the primary degradation pathway of proteins, leads to issues ranging from manufacturing failure to immunological response and to loss of therapeutic activity. Using our spatial aggregation propensity tool as a first step to a rational design approach to identify aggregation-prone regions, biobetters of rituximab have been produced with enhanced stability by introducing site-specific mutations. Significant stabilization against aggregation was achieved for rituximab with no decrease in its binding affinity to the antigen. PMID:26096711

  5. Towards the Rational Design of Nanoparticle Catalysts

    NASA Astrophysics Data System (ADS)

    Dash, Priyabrat

    This research is focused on development of routes towards the rational design of nanoparticle catalysts. Primarily, it is focused on two main projects; (1) the use of imidazolium-based ionic liquids (ILs) as greener media for the design of quasi-homogeneous nanoparticle catalysts and (2) the rational design of heterogeneous-supported nanoparticle catalysts from structured nanoparticle precursors. Each project has different studies associated with the main objective of the design of nanoparticle catalysts. In the first project, imidazolium-based ionic liquids have been used for the synthesis of nanoparticle catalysts. In particular, studies on recyclability, reuse, mode-of-stability, and long-term stability of these ionic-liquid supported nanoparticle catalysts have been done; all of which are important factors in determining the overall "greenness" of such synthetic routes. Three papers have been published/submitted for this project. In the first publication, highly stable polymer-stabilized Au, Pd and bimetallic Au-Pd nanoparticle catalysts have been synthesized in imidazolium-based 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) ionic liquid (Journal of Molecular Catalysis A: Chemical, 2008, 286, 114). The resulting nanoparticles were found to be effective and selective quasi-homogeneous catalysts towards a wide-range of hydrogenation reactions and the catalyst solution was reused for further catalytic reactions with minimal loss in activity. The synthesis of very pure and clean ILs has allowed a platform to study the effects of impurities in the imidazolium ILs on nanoparticle stability. In a later study, a new mode of stabilization was postulated where the presence of low amounts of 1-methylimidazole has substantial effects on the resulting stability of Au and Pd-Au nanoparticles in these ILs (Chemical Communications, 2009, 812). In further continuation of this study, a comparative study involving four stabilization protocols for nanoparticle

  6. Rationality.

    PubMed

    Sosis, Clifford; Bishop, Michael A

    2014-01-01

    A theory of rationality is a theory that evaluates instances of reasoning as rational, irrational, or (ir)rational to some degree. Theories can be categorized as rule-based or consequentialist. Rule-based theories say that rational reasoning accords with certain rules (e.g., of logic or probability). Consequentialist theories say that rational reasoning tends to produce good consequences. For instance, the reliabilist takes rationality to be reasoning that tends to produce mostly true beliefs. The pragmatist takes it to be reasoning that tends to produce mostly useful beliefs. This article reviews some of the features and the challenges of rule-based, reliabilist, and pragmatist theories of rationality. WIREs Cogn Sci 2014, 5:27-37. doi: 10.1002/wcs.1263 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. PMID:26304295

  7. Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs.

    PubMed

    Ashour, Ahmed; El-Sharkawy, Saleh; Amer, Mohamed; Abdel Bar, Fatma; Katakura, Yoshinori; Miyamoto, Tomofumi; Toyota, Nozomi; Bang, Tran Hai; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2014-01-01

    Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12-C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα. PMID:24326278

  8. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

    NASA Astrophysics Data System (ADS)

    Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya

    2012-02-01

    Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O → Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg-1 platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.

  9. Rationally designing the mechanical properties of protein hydrogels

    NASA Astrophysics Data System (ADS)

    Cao, Yi

    Naturally occurring biomaterials possess diverse mechanical properties, which are critical to their unique biological functions. However, it remains challenging to rationally control the mechanical properties of synthetic biomaterials. Here we provide a bottom-up approach to rationally design the mechanical properties of protein-based hydrogels. We first use atomic fore microscope (AFM) based single-molecule force spectroscopy to characterize the mechanical stability of individual protein building blocks. We then rationally design the mechanical properties of hydrogels by selecting different combination of protein building blocks of known mechanical properties. As a proof-of-principle, we demonstrate the engineering of hydrogels of distinct extensibility and toughness. This simple combinatorial approach allows direct translation of the mechanical properties of proteins from the single molecule level to the macroscopic level and represents an important step towards rationally designing the mechanical properties of biomaterials.

  10. Rational drug design paradigms: the odyssey for designing better drugs.

    PubMed

    Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

    2015-01-01

    Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules. PMID:25747445

  11. Rational Design of Immunostimulatory siRNAs

    PubMed Central

    Gantier, Michael P; Tong, Stephen; Behlke, Mark A; Irving, Aaron T; Lappas, Martha; Nilsson, Ulrika W; Latz, Eicke; McMillan, Nigel AJ; Williams, Bryan RG

    2010-01-01

    Short-interfering RNAs (siRNAs) have engendered much enthusiasm for their ability to silence the expression of specific genes. However, it is now well established that siRNAs, depending on their sequence, can be variably sensed by the innate immune system through recruitment of toll-like receptors 7 and 8 (TLR7/8). Here, we aimed to identify sequence-based modifications allowing for the design of bifunctional siRNAs with both proinflammatory and specific silencing activities, and with potentially increased therapeutic benefits. We found that the introduction of a micro-RNA (miRNA)-like nonpairing uridine-bulge in the passenger strand robustly increased immunostimulatory activity on human immune cells. This sequence modification had no effect on the silencing efficiency of the siRNA. Increased immunostimulation with the uridine-bulge design was specific to human cells, and conserved silencing efficiency required a Dicer-substrate scaffold. The increased cytokine production with the uridine-bulge design resulted in enhanced protection against Semliki Forest virus (SFV) infection, in viral assays. Thus, we characterize a design scaffold applicable to any given siRNA sequence, that results in increased innate immune activation without affecting gene silencing. Our data suggest that this sequence modification coupled with structural modification differentially recruits human TLR8 over TLR7, and could have potential application in antiviral therapies. PMID:20125126

  12. Computational approaches for rational design of proteins with novel functionalities

    PubMed Central

    Tiwari, Manish Kumar; Singh, Ranjitha; Singh, Raushan Kumar; Kim, In-Won; Lee, Jung-Kul

    2012-01-01

    Proteins are the most multifaceted macromolecules in living systems and have various important functions, including structural, catalytic, sensory, and regulatory functions. Rational design of enzymes is a great challenge to our understanding of protein structure and physical chemistry and has numerous potential applications. Protein design algorithms have been applied to design or engineer proteins that fold, fold faster, catalyze, catalyze faster, signal, and adopt preferred conformational states. The field of de novo protein design, although only a few decades old, is beginning to produce exciting results. Developments in this field are already having a significant impact on biotechnology and chemical biology. The application of powerful computational methods for functional protein designing has recently succeeded at engineering target activities. Here, we review recently reported de novo functional proteins that were developed using various protein design approaches, including rational design, computational optimization, and selection from combinatorial libraries, highlighting recent advances and successes. PMID:24688643

  13. Rational Design of Metal Ion Sequestering Agents

    SciTech Connect

    Raymond, Kenneth N.

    2000-09-30

    The discriminate bonding of metal ions is a challenge to the synthetic chemist and a phenomenon of considerable practical importance.1 An important feature of many technical applications is the specific or preferential binding of a single metal ion in the presence of many metals. Examples range from large-volume uses (e.g. ferric EDTA as a plant food, calcium complexing agents as water softeners or anticaking formulations) to very high technology applications (technetium complexation in radiopharmaceuticals, synthetic metalloenzymes). We are interested in efficient and discriminate binding of actinides for waste stream remediation. Actinides represent a major and long-lived contaminant in nuclear waste. While the separation of actinides from other radioactive components of waste, such as Sr and Cs, is relatively well established, the separation of actinides from each other and in complex solutions (e.g. those found in tank wastes) is not as well resolved. The challenge of designing metal-specific (actinide) ligands is facilitated by examples from nature. Bacteria synthesize Fe(III)-specific ligands, called siderophores, to sequester Fe(III) from the environment and return it to the cell. The similarities between Fe(III) and Pu(IV) (their charge-to-size ratios and acidity), make the siderophores prototypical for designing actinide-specific ligands. The chelating groups present in siderophores are usually hydroxamic acids and catecholamides. We have developed derivatives of these natural products which have improved properties. The catechol derivatives are the 2,3-dihydroxyterephthalamides (TAMs), and 3,4-dihydroxysulfonamides (SFAMs), and the hydroxamic acid derivatives are three isomers of hydroxypyridinones, 1,2- HOPO, 3,2-HOPO, and 3,4-HOPO. All of these ligands are attached to molecular backbones by amides and a very important feature of HOPO and CAM ligands is a strong hydrogen bonds formed between the amide proton and the adjacent phenolic oxygen in the metal

  14. Structure-Based, Rational Design of T Cell Receptors

    PubMed Central

    Zoete, V.; Irving, M.; Ferber, M.; Cuendet, M. A.; Michielin, O.

    2013-01-01

    Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157–165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8+ T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, KD = ∼1 − 5 μM. Beyond the affinity threshold at KD < 1 μM we observed an attenuation in cellular function, in line with the “half-life” model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method

  15. Serendipity in Cancer Drug Discovery: Rational or Coincidence?

    PubMed

    Prasad, Sahdeo; Gupta, Subash C; Aggarwal, Bharat B

    2016-06-01

    Novel drug development leading to final approval by the US FDA can cost as much as two billion dollars. Why the cost of novel drug discovery is so expensive is unclear, but high failure rates at the preclinical and clinical stages are major reasons. Although therapies targeting a given cell signaling pathway or a protein have become prominent in drug discovery, such treatments have done little in preventing or treating any disease alone because most chronic diseases have been found to be multigenic. A review of the discovery of numerous drugs currently being used for various diseases including cancer, diabetes, cardiovascular, pulmonary, and autoimmune diseases indicates that serendipity has played a major role in the discovery. In this review we provide evidence that rational drug discovery and targeted therapies have minimal roles in drug discovery, and that serendipity and coincidence have played and continue to play major roles. The primary focus in this review is on cancer-related drug discovery. PMID:27083322

  16. Refolding of proteins from inclusion bodies: rational design and recipes.

    PubMed

    Basu, Anindya; Li, Xiang; Leong, Susanna Su Jan

    2011-10-01

    The need to develop protein biomanufacturing platforms that can deliver proteins quickly and cost-effectively is ever more pressing. The rapid rate at which genomes can now be sequenced demands efficient protein production platforms for gene function identification. There is a continued need for the biotech industry to deliver new and more effective protein-based drugs to address new diseases. Bacterial production platforms have the advantage of high expression yields, but insoluble expression of many proteins necessitates the development of diverse and optimised refolding-based processes. Strategies employed to eliminate insoluble expression are reviewed, where it is concluded that inclusion bodies are difficult to eliminate for various reasons. Rational design of refolding systems and recipes are therefore needed to expedite production of recombinant proteins. This review article discusses efforts towards rational design of refolding systems and recipes, which can be guided by the development of refolding screening platforms that yield both qualitative and quantitative information on the progression of a given refolding process. The new opportunities presented by light scattering technologies for developing rational protein refolding buffer systems which in turn can be used to develop new process designs armed with better monitoring and controlling functionalities are discussed. The coupling of dynamic and static light scattering methodologies for incorporation into future bioprocess designs to ensure delivery of high-quality refolded proteins at faster rates is also discussed. PMID:21822901

  17. Rational design and synthesis of semi-conducting polymers.

    SciTech Connect

    Wong, Bryan Matthew; Reeder, Craig; Cordaro, Joseph Gabriel

    2010-12-01

    A rational approach was used to design polymeric materials for thin-film electronics applications, whereby theoretical modeling was used to determine synthetic targets. Time-dependent density functional theory calculations were used as a tool to predict the electrical properties of conjugated polymer systems. From these results, polymers with desirable energy levels and band-gaps were designed and synthesized. Measurements of optoelectronic properties were performed on the synthesized polymers and the results were compared to those of the theoretical model. From this work, the efficacy of the model was evaluated and new target polymers were identified.

  18. Rational design of inorganic dielectric materials with expected permittivity

    PubMed Central

    Xie, Congwei; Oganov, Artem R.; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-01-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up. PMID:26617342

  19. Evolving protocells to prototissues: rational design of a missing link.

    PubMed

    Mantri, Shiksha; Sapra, K Tanuj

    2013-10-01

    Realization of a functional artificial cell, the so-called protocell, is a major challenge posed by synthetic biology. A subsequent goal is to use the protocellular units for the bottom-up assembly of prototissues. There is, however, a looming chasm in our knowledge between protocells and prototissues. In the present paper, we give a brief overview of the work on protocells to date, followed by a discussion on the rational design of key structural elements specific to linking two protocellular bilayers. We propose that designing synthetic parts capable of simultaneous insertion into two bilayers may be crucial in the hierarchical assembly of protocells into a functional prototissue. PMID:24059502

  20. Rational design of inorganic dielectric materials with expected permittivity.

    PubMed

    Xie, Congwei; Oganov, Artem R; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-01-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up. PMID:26617342

  1. Rational design of inorganic dielectric materials with expected permittivity

    NASA Astrophysics Data System (ADS)

    Xie, Congwei; Oganov, Artem R.; Dong, Dong; Liu, Ning; Li, Duan; Debela, Tekalign Terfa

    2015-11-01

    Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up.

  2. Concepts and software for a rational design of polynucleotide probes.

    PubMed

    Moraru, Cristina; Moraru, Gabriel; Fuchs, Bernhard M; Amann, Rudolf

    2011-02-01

    Fluorescence in situ hybridization (FISH) of genes and mRNA is most often based on polynucleotide probes. However, so far there was no published framework for the rational design of polynucleotide probes. The well-established concepts for oligonucleotide probe design cannot be transferred to polynucleotides. Due to the high allele diversity of genes, a single probe is not sufficient to detect all alleles of a gene. Therefore, the main objective of this study was to develop a concept and software (PolyPro) for rational design of polynucleotide probe mixes to target particular genes. PolyPro consists of three modules: a GenBank Taxonomy Extractor (GTE), a Polynucleotide Probe Designer (PPD) and a Hybridization Parameters Calculator (HPC). The new concept proposes the construction of defined polynucleotide mixes to target the habitat specific sequence diversity of a particular gene. The concept and the software are intended as a first step towards a more frequent application of polynucleotides for in situ identification of mRNA and genes in environmental microbiology. PMID:23761233

  3. Rational Design of Plasmonic Nanoparticles for Enhanced Cavitation and Cell Perforation.

    PubMed

    Lachaine, Rémi; Boutopoulos, Christos; Lajoie, Pierre-Yves; Boulais, Étienne; Meunier, Michel

    2016-05-11

    Metallic nanoparticles are routinely used as nanoscale antenna capable of absorbing and converting photon energy with subwavelength resolution. Many applications, notably in nanomedicine and nanobiotechnology, benefit from the enhanced optical properties of these materials, which can be exploited to image, damage, or destroy targeted cells and subcellular structures with unprecedented precision. Modern inorganic chemistry enables the synthesis of a large library of nanoparticles with an increasing variety of shapes, composition, and optical characteristic. However, identifying and tailoring nanoparticles morphology to specific applications remains challenging and limits the development of efficient nanoplasmonic technologies. In this work, we report a strategy for the rational design of gold plasmonic nanoshells (AuNS) for the efficient ultrafast laser-based nanoscale bubble generation and cell membrane perforation, which constitute one of the most crucial challenges toward the development of effective gene therapy treatments. We design an in silico rational design framework that we use to tune AuNS morphology to simultaneously optimize for the reduction of the cavitation threshold while preserving the particle structural integrity. Our optimization procedure yields optimal AuNS that are slightly detuned compared to their plasmonic resonance conditions with an optical breakdown threshold 30% lower than randomly selected AuNS and 13% lower compared to similarly optimized gold nanoparticles (AuNP). This design strategy is validated using time-resolved bubble spectroscopy, shadowgraphy imaging and electron microscopy that confirm the particle structural integrity and a reduction of 51% of the cavitation threshold relative to optimal AuNP. Rationally designed AuNS are finally used to perforate cancer cells with an efficiency of 61%, using 33% less energy compared to AuNP, which demonstrate that our rational design framework is readily transferable to a cell environment

  4. Using Fitness Landscapes for Rational Hepatitis C Immunogen Design

    NASA Astrophysics Data System (ADS)

    Hart, Gregory; Ferguson, Andrew

    2015-03-01

    Hepatitis C virus afflicts 170 million people worldwide, 2-3% of the global population. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic, particularly in the developing world where expensive drug therapies are unavailable. Despite 20 years of research, the high mutability of the virus, and lack of knowledge of what constitutes effective immune responses, have impeded development of an effective vaccine. Coupling data mining of sequence databases with the Potts model, we have developed a computational approach to systematically identify viral vulnerabilities and perform rational design of vaccine immunogens. We applied our approach to the nonstructural proteins NS3, NSA, NSA, and NSB which are crucial for viral replication.The predictions of our model are in good accord with experimental measurements and clinical observations, and we have used our model to design immunogen candidates to elicit T-cell responses against vulnerable regions of theseviral proteins.

  5. Beyond directed evolution - semi-rational protein engineering and design

    PubMed Central

    Lutz, Stefan

    2010-01-01

    Over the last two decades, directed evolution has transformed the field of protein engineering. The advances in understanding protein structure and function, in no insignificant part a result of directed evolution studies, are increasingly empowering scientists and engineers to device more effective methods for manipulating and tailoring biocatalysts. Abandoning large combinatorial libraries, the focus has shifted to small, functionally-rich libraries and rational design. A critical component to the success of these emerging engineering strategies are computational tools for the evaluation of protein sequence datasets and the analysis of conformational variations of amino acids in proteins. Highlighting the opportunities and limitations of such approaches, this review focuses on recent engineering and design examples that require screening or selection of small libraries. PMID:20869867

  6. Principles underlying rational design of live attenuated influenza vaccines

    PubMed Central

    Jang, Yo Han

    2012-01-01

    Despite recent innovative advances in molecular virology and the developments of vaccines, influenza virus remains a serious burden for human health. Vaccination has been considered a primary countermeasure for prevention of influenza infection. Live attenuated influenza vaccines (LAIVs) are particularly attracting attention as an effective strategy due to several advantages over inactivated vaccines. Cold-adaptation, as a classical means for attenuating viral virulence, has been successfully used for generating safe and effective donor strains of LAIVs against seasonal epidemics and occasional pandemics. Recently, the advent of reverse genetics technique expedited a variety of rational strategies to broaden the pool of LAIVs. Considering the breadth of antigenic diversity of influenza virus, the pool of LAIVs is likely to equip us with better options for controlling influenza pandemics. With a brief reflection on classical attenuating strategies used at the initial stage of development of LAIVs, especially on the principles underlying the development of cold-adapted LAIVs, we further discuss and outline other attenuation strategies especially with respect to the rationales for attenuation, and their practicality for mass production. Finally, we propose important considerations for a rational vaccine design, which will provide us with practical guidelines for improving the safety and effectiveness of LAIVs. PMID:23596576

  7. Rational design of functional and tunable oscillating enzymatic networks

    NASA Astrophysics Data System (ADS)

    Semenov, Sergey N.; Wong, Albert S. Y.; van der Made, R. Martijn; Postma, Sjoerd G. J.; Groen, Joost; van Roekel, Hendrik W. H.; de Greef, Tom F. A.; Huck, Wilhelm T. S.

    2015-02-01

    Life is sustained by complex systems operating far from equilibrium and consisting of a multitude of enzymatic reaction networks. The operating principles of biology's regulatory networks are known, but the in vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of synthetic systems showing autonomous behaviour. Here, we present a strategy for the rational design of programmable functional reaction networks that exhibit dynamic behaviour. We demonstrate that a network built around autoactivation and delayed negative feedback of the enzyme trypsin is capable of producing sustained oscillating concentrations of active trypsin for over 65 h. Other functions, such as amplification, analog-to-digital conversion and periodic control over equilibrium systems, are obtained by linking multiple network modules in microfluidic flow reactors. The methodology developed here provides a general framework to construct dissipative, tunable and robust (bio)chemical reaction networks.

  8. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  9. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID:26022561

  10. Rational design of functional and tunable oscillating enzymatic networks.

    PubMed

    Semenov, Sergey N; Wong, Albert S Y; van der Made, R Martijn; Postma, Sjoerd G J; Groen, Joost; van Roekel, Hendrik W H; de Greef, Tom F A; Huck, Wilhelm T S

    2015-02-01

    Life is sustained by complex systems operating far from equilibrium and consisting of a multitude of enzymatic reaction networks. The operating principles of biology's regulatory networks are known, but the in vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of synthetic systems showing autonomous behaviour. Here, we present a strategy for the rational design of programmable functional reaction networks that exhibit dynamic behaviour. We demonstrate that a network built around autoactivation and delayed negative feedback of the enzyme trypsin is capable of producing sustained oscillating concentrations of active trypsin for over 65 h. Other functions, such as amplification, analog-to-digital conversion and periodic control over equilibrium systems, are obtained by linking multiple network modules in microfluidic flow reactors. The methodology developed here provides a general framework to construct dissipative, tunable and robust (bio)chemical reaction networks. PMID:25615670

  11. Toward rational design of electrical stimulation strategies for epilepsy control.

    PubMed

    Sunderam, Sridhar; Gluckman, Bruce; Reato, Davide; Bikson, Marom

    2010-01-01

    Electrical stimulation is emerging as a viable alternative for patients with epilepsy whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy, namely, seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy. PMID:19926525

  12. Toward rational design of electrical stimulation strategies for epilepsy control

    PubMed Central

    Sunderam, Sridhar; Gluckman, Bruce; Reato, Davide; Bikson, Marom

    2009-01-01

    Electrical stimulation is emerging as a viable alternative for epilepsy patients whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy: namely seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy. PMID:19926525

  13. Rational design of the exchange-spring permanent magnet.

    PubMed

    Jiang, J S; Bader, S D

    2014-02-12

    The development of the optimal exchange-spring permanent magnet balances exchange hardening, magnetization enhancement, and the feasibility of scalable fabrication. These requirements can be met with a rational design of the microstructural characteristics. The magnetization processes in several model exchange-spring structures with different geometries have been analyzed with both micromagnetic simulations and nucleation theory. The multilayer geometry and the soft-cylinders-in-hard-matrix geometry have the highest achievable figure of merit (BH)max, while the soft-spheres-in-hard-matrix geometry has the lowest upper limit for (BH)max. The cylindrical geometry permits the soft phase to be larger and does not require strict size control. Exchange-spring permanent magnets based on the cylindrical geometry may be amenable to scaled-up fabrication. PMID:24469386

  14. Rational design of high affinity tachykinin NK1 receptor antagonists.

    PubMed

    Boyle, S; Guard, S; Higginbottom, M; Horwell, D C; Howson, W; McKnight, A T; Martin, K; Pritchard, M C; O'Toole, J; Raphy, J

    1994-05-01

    The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv. PMID:7922147

  15. Rational clinical trial design for antibody mediated renal allograft injury.

    PubMed

    Sandal, Shaifali; Zand, Martin S

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  16. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  17. Rational Co-Design of Polymer Dielectrics for Energy Storage.

    PubMed

    Mannodi-Kanakkithodi, Arun; Treich, Gregory M; Huan, Tran Doan; Ma, Rui; Tefferi, Mattewos; Cao, Yang; Sotzing, Gregory A; Ramprasad, Rampi

    2016-08-01

    Although traditional materials discovery has historically benefited from intuition-driven experimental approaches and serendipity, computational strategies have risen in prominence and proven to be a powerful complement to experiments in the modern materials research environment. It is illustrated here how one may harness a rational co-design approach-involving synergies between high-throughput computational screening and experimental synthesis and testing-with the example of polymer dielectrics design for electrostatic energy storage applications. Recent co-design efforts that can potentially enable going beyond present-day "standard" polymer dielectrics (such as biaxially oriented polypropylene) are highlighted. These efforts have led to the identification of several new organic polymer dielectrics within known generic polymer subclasses (e.g., polyurea, polythiourea, polyimide), and the recognition of the untapped potential inherent in entirely new and unanticipated chemical subspaces offered by organometallic polymers. The challenges that remain and the need for additional methodological developments necessary to further strengthen the co-design concept are then presented. PMID:27167752

  18. Potential of fragment recombination for rational design of proteins.

    PubMed

    Eisenbeis, Simone; Proffitt, William; Coles, Murray; Truffault, Vincent; Shanmugaratnam, Sooruban; Meiler, Jens; Höcker, Birte

    2012-03-01

    It is hypothesized that protein domains evolved from smaller intrinsically stable subunits via combinatorial assembly. Illegitimate recombination of fragments that encode protein subunits could have quickly led to diversification of protein folds and their functionality. This evolutionary concept presents an attractive strategy to protein engineering, e.g., to create new scaffolds for enzyme design. We previously combined structurally similar parts from two ancient protein folds, the (βα)(8)-barrel and the flavodoxin-like fold. The resulting "hopeful monster" differed significantly from the intended (βα)(8)-barrel fold by an extra β-strand in the core. In this study, we ask what modifications are necessary to form the intended structure and what potential this approach has for the rational design of functional proteins. Guided by computational design, we optimized the interface between the fragments with five targeted mutations yielding a stable, monomeric protein whose predicted structure was verified experimentally. We further tested binding of a phosphorylated compound and detected that some affinity was already present due to an intact phosphate-binding site provided by one fragment. The affinity could be improved quickly to the level of natural proteins by introducing two additional mutations. The study illustrates the potential of recombining protein fragments with unique properties to design new and functional proteins, offering both a possible pathway of protein evolution and a protocol to rapidly engineer proteins for new applications. PMID:22329686

  19. Rational use of water in trickle irrigation design.

    NASA Astrophysics Data System (ADS)

    Saad, J. C. C.; da Silva Junior, H. M.

    2012-04-01

    In trickle irrigation systems, the design is based on the pre-established emission uniformity (EU) which is the combined result of the equipment characteristics and its hydraulic configuration. However, this desired value of the EU may not be confirmed by the final project (in field conditions) and neither by the yield uniformity. However, the most important is to assure yield uniformity with rational use of water. The hypotheses of this research were: a) the EU of a trickle irrigation system at field conditions is equal to the emission uniformity pre-established in the design; b) EU has always the lowest value when compared with other indicators of uniformity; c) the discharge variation coefficient is not equal to production variation coefficient in the operational unit; d) the productivity variation coefficient is more dependent on water depth applied than the EU. This study aimed to evaluate the relationships among EU used in the irrigation system design, water depth applied and the final yield uniformity. The uniformity indicators evaluated were: EU, distribution uniformity (UD) and the index proposed by Barragan & Wu (2005). They were compared estimating the performance of a trickle irrigation system applied in a citrus orchard with dimensions of 400m x 600m. The design of the irrigation system was optimized by a Linear Programming model. The tree rows were leveled in the larger direction and the spacing adopted in the orchard was 7m x 4m. The manifold line was always operating on a slope condition. The sensitivity analysis involved different slopes, 0, 3, 6, 9 and 12%, and different values of emission uniformity, 60, 70, 75, 80, 85, 90 and 94%. The citrus yield uniformity was evaluated by the variation coefficient. The emission uniformity (EU) after design differed from the EU pre-established, more sharply in the initial values lower than 90%. Comparing the uniformity indexes, the EU always generated lower values when compared with the UD and with the index

  20. Rational Design of MMP Degradable Peptide-Based Supramolecular Filaments

    PubMed Central

    2015-01-01

    One-dimensional nanostructures formed by self-assembly of small molecule peptides have been extensively explored for use as biomaterials in various biomedical contexts. However, unlike individual peptides that can be designed to be specifically degradable by enzymes/proteases of interest, their self-assembled nanostructures, particularly those rich in β-sheets, are generally resistant to enzymatic degradation because the specific cleavage sites are often embedded inside the nanostructures. We report here on the rational design of β-sheet rich supramolecular filaments that can specifically dissociate into less stable micellar assemblies and monomers upon treatment with matrix metalloproteases-2 (MMP-2). Through linkage of an oligoproline segment to an amyloid-derived peptide sequence, we first synthesized an amphiphilic peptide that can undergo a rapid morphological transition in response to pH variations. We then used MMP-2 specific peptide substrates as multivalent cross-linkers to covalently fix the amyloid-like filaments in the self-assembled state at pH 4.5. Our results show that the cross-linked filaments are stable at pH 7.5 but gradually break down into much shorter filaments upon cleavage of the peptidic cross-linkers by MMP-2. We believe that the reported work presents a new design platform for the creation of amyloid-like supramolecular filaments responsive to enzymatic degradation. PMID:24611531

  1. Rationally designed molecular beacons for bioanalytical and biomedical applications.

    PubMed

    Zheng, Jing; Yang, Ronghua; Shi, Muling; Wu, Cuichen; Fang, Xiaohong; Li, Yinhui; Li, Jishan; Tan, Weihong

    2015-05-21

    Nucleic acids hold promise as biomolecules for future applications in biomedicine and biotechnology. Their well-defined structures and compositions afford unique chemical properties and biological functions. Moreover, the specificity of hydrogen-bonded Watson-Crick interactions allows the construction of nucleic acid sequences with multiple functions. In particular, the development of nucleic acid probes as essential molecular engineering tools will make a significant contribution to advancements in biosensing, bioimaging and therapy. The molecular beacon (MB), first conceptualized by Tyagi and Kramer in 1996, is an excellent example of a double-stranded nucleic acid (dsDNA) probe. Although inactive in the absence of a target, dsDNA probes can report the presence of a specific target through hybridization or a specific recognition-triggered change in conformation. MB probes are typically fluorescently labeled oligonucleotides that range from 25 to 35 nucleotides (nt) in length, and their structure can be divided into three components: stem, loop and reporter. The intrinsic merit of MBs depends on predictable design, reproducibility of synthesis, simplicity of modification, and built-in signal transduction. Using resonance energy transfer (RET) for signal transduction, MBs are further endowed with increased sensitivity, rapid response and universality, making them ideal for chemical sensing, environmental monitoring and biological imaging, in contrast to other nucleic acid probes. Furthermore, integrating MBs with targeting ligands or molecular drugs can substantially support their in vivo applications in theranositics. In this review, we survey advances in bioanalytical and biomedical applications of rationally designed MBs, as they have evolved through the collaborative efforts of many researchers. We first discuss improvements to the three components of MBs: stem, loop and reporter. The current applications of MBs in biosensing, bioimaging and therapy will then

  2. Rational material design for ultrafast rechargeable lithium-ion batteries.

    PubMed

    Tang, Yuxin; Zhang, Yanyan; Li, Wenlong; Ma, Bing; Chen, Xiaodong

    2015-10-01

    Rechargeable lithium-ion batteries (LIBs) are important electrochemical energy storage devices for consumer electronics and emerging electrical/hybrid vehicles. However, one of the formidable challenges is to develop ultrafast charging LIBs with the rate capability at least one order of magnitude (>10 C) higher than that of the currently commercialized LIBs. This tutorial review presents the state-of-the-art developments in ultrafast charging LIBs by the rational design of materials. First of all, fundamental electrochemistry and related ionic/electronic conduction theories identify that the rate capability of LIBs is kinetically limited by the sluggish solid-state diffusion process in electrode materials. Then, several aspects of the intrinsic materials, materials engineering and processing, and electrode materials architecture design towards maximizing both ionic and electronic conductivity in the electrode with a short diffusion length are deliberated. Finally, the future trends and perspectives for the ultrafast rechargeable LIBs are discussed. Continuous rapid progress in this area is essential and urgent to endow LIBs with ultrafast charging capability to meet huge demands in the near future. PMID:25857819

  3. Rational Co-Design of Polymer Dielectrics for Energy Storage

    NASA Astrophysics Data System (ADS)

    Mannodi-Kanakkithodi, Arun; Tran, Huan; Pilania, Ghanshyam; Lookman, Turab; Ramprasad, Rampi

    While intuition-driven experiments and serendipity have guided traditional materials discovery, computational strategies have become increasingly important and a powerful complement to experiments in modern day materials research. With the example of polymer dielectrics for electrostatic energy storage applications, we demonstrate how a rational co-design approach--involving synergies between high-throughput computational screening and experimental synthesis and testing--can be harnessed for quick and efficient discovery. We highlight recent co-design efforts that can potentially lead to replacement of present-day ``standard'' polymer dielectrics (such as biaxially oriented polypropylene) not only by new organic polymer candidates within known generic polymer subclasses (e.g., polyurea, polythiourea, polyimide), but also by organometallic polymers, a hitherto untapped but promising chemical subspace. We also discuss the utilization of vast computational data (generated in the aforementioned process) towards the development of statistical learning models for relevant properties of dielectric polymers, which can further accelerate the guidance to experiments and thus the successful discovery of new materials.

  4. Protocol for rational design of covalently interacting inhibitors.

    PubMed

    Schmidt, Thomas C; Welker, Armin; Rieger, Max; Sahu, Prabhat K; Sotriffer, Christoph A; Schirmeister, Tanja; Engels, Bernd

    2014-10-20

    The inhibition potencies of covalent inhibitors mainly result from the formation of a covalent bond to the enzyme during the inhibition mechanism. This class of inhibitors has essentially been ignored in previous target-directed drug discovery projects because of concerns about possible side effects. However, their advantages, such as higher binding energies and longer drug-target residence times moved them into the focus of recent investigations. While the rational design of non-covalent inhibitors became standard the corresponding design of covalent inhibitors is still in its early stages. Potent covalent inhibitors can be retrieved from large compound libraries by covalent docking approaches but protocols are missing that can reliably predict the influence of variations in the substitution pattern on the affinity and/or reactivity of a given covalent inhibitor. Hence, the wanted property profile can only be obtained from trial-and-error proceedings. This paper presents an appropriate protocol which is able to predict improved covalent inhibitors. It uses hybrid approaches, which mix quantum mechanical (QM) and molecular mechanical (MM) methods to predict variations in the reactivity of the inhibitor. They are also used to compute the required information about the non-covalent enzyme-inhibitor complex. Docking tools are employed to improve the inhibitor with respect to the non-covalent interactions formed in the binding site. PMID:25251382

  5. Rational design and synthesis of excavated trioctahedral Au nanocrystals

    NASA Astrophysics Data System (ADS)

    Chen, Qiaoli; Jia, Yanyan; Shen, Wei; Xie, Shuifen; Yang, Yanan; Cao, Zhenming; Xie, Zhaoxiong; Zheng, Lansun

    2015-06-01

    Excavated polyhedral nanostructures, possessing the features of high surface area and well-defined surface structure with a specific crystal facet and avoidance of aggregation, could be one of the best choices for the purpose of reducing consumption and improving performance of noble metals in many application fields. However, the formation of the excavated structures is thermodynamically unfavourable and its rational synthesis is far beyond our knowledge. In this work, taking overgrowth of Pd onto trioctahedral Au nanocrystals as a model, we present a deep insight study for synthesizing an excavated structure relying on the protection role of surfactants under suitable crystal growth kinetics. Based on the abovementioned understanding, we designed a simple and effective strategy to synthesize Au nanocrystals with excavated trioctahedral structure in one step. Due to the novel feature of the excavated structure and exposed high energy {110} facets, excavated trioctahedral Au NCs exhibited optical extinction at the near-infrared region and showed high catalytic activity towards the reduction of p-nitrophenol. Moreover, the synthetic strategy can be extended to the synthesis of excavated Au-Pd alloys.Excavated polyhedral nanostructures, possessing the features of high surface area and well-defined surface structure with a specific crystal facet and avoidance of aggregation, could be one of the best choices for the purpose of reducing consumption and improving performance of noble metals in many application fields. However, the formation of the excavated structures is thermodynamically unfavourable and its rational synthesis is far beyond our knowledge. In this work, taking overgrowth of Pd onto trioctahedral Au nanocrystals as a model, we present a deep insight study for synthesizing an excavated structure relying on the protection role of surfactants under suitable crystal growth kinetics. Based on the abovementioned understanding, we designed a simple and effective

  6. Rationally designed polyimides for high-energy density capacitor applications.

    PubMed

    Ma, Rui; Baldwin, Aaron F; Wang, Chenchen; Offenbach, Ido; Cakmak, Mukerrem; Ramprasad, Rampi; Sotzing, Gregory A

    2014-07-01

    Development of new dielectric materials is of great importance for a wide range of applications for modern electronics and electrical power systems. The state-of-the-art polymer dielectric is a biaxially oriented polypropylene (BOPP) film having a maximal energy density of 5 J/cm(3) and a high breakdown field of 700 MV/m, but with a limited dielectric constant (∼2.2) and a reduced breakdown strength above 85 °C. Great effort has been put into exploring other materials to fulfill the demand of continuous miniaturization and improved functionality. In this work, a series of polyimides were investigated as potential polymer materials for this application. Polyimide with high dielectric constants of up to 7.8 that exhibits low dissipation factors (<1%) and high energy density around 15 J/cm(3), which is 3 times that of BOPP, was prepared. Our syntheses were guided by high-throughput density functional theory calculations for rational design in terms of a high dielectric constant and band gap. Correlations of experimental and theoretical results through judicious variations of polyimide structures allowed for a clear demonstration of the relationship between chemical functionalities and dielectric properties. PMID:24911181

  7. Rational design of enhanced photoresistance in a photoswitchable fluorescent protein

    NASA Astrophysics Data System (ADS)

    Duan, Chenxi; Byrdin, Martin; El Khatib, Mariam; Henry, Xavier; Adam, Virgile; Bourgeois, Dominique

    2015-03-01

    Fluorescent proteins are particularly susceptible to photobleaching, the permanent loss of fluorescence emission resulting from photodestruction of the chromophore. In the case of Reversibly Switchable Fluorescent Proteins (RSFPs), which can be switched back and forth between a non-fluorescent and a fluorescent state, the achievable number of switching cycles is limited by photobleaching, a process known as photofatigue. Photofatigue has become a crucial limitation in a number of advanced applications based on repeated photoswitching of RSFPs, notably in the field of super-resolution fluorescence microscopy. Here, based on our previous structural investigation of photobleaching mechanisms in IrisFP, an RSFP also capable of green-to-red photoconversion, we present the rational design of a single-mutant IrisFP-M159A that displays considerably enhanced photostability. The results suggest that, under moderate illumination intensities, photobleaching of IrisFP-like Anthozoan fluorescent proteins such as EosFP, Dendra or Dronpa derivatives is mainly driven by an oxygen-dependent mechanism resulting in the irreversible sulfoxidation of methionine 159. The photofatigue decay profiles of IrisFP and its photoresistant mutant IrisFP-M159A were investigated in different experimental conditions, in vitro and in cellulo. Although the performance of the mutant was found to be always superior, the results showed switching behaviors strongly dependent on the nanoenvironment. Thus, in general, assessment of photostability and switching properties of RSFPs should be carried out in real experimental conditions.

  8. In silico ADME/T modelling for rational drug design.

    PubMed

    Wang, Yulan; Xing, Jing; Xu, Yuan; Zhou, Nannan; Peng, Jianlong; Xiong, Zhaoping; Liu, Xian; Luo, Xiaomin; Luo, Cheng; Chen, Kaixian; Zheng, Mingyue; Jiang, Hualiang

    2015-11-01

    In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed. PMID:26328949

  9. Patterning symmetry in the rational design of colloidal crystals.

    PubMed

    Romano, Flavio; Sciortino, Francesco

    2012-01-01

    Colloidal particles have the right size to form ordered structures with periodicities comparable to the wavelength of visible light. The tantalizing colours of precious opals and the colour of some species of birds are examples of polycrystalline colloidal structures found in nature. Driven by the demands of several emergent technologies, efforts have been made to develop efficient, self-assembly-based methodologies for generating colloidal single crystals with well-defined morphologies. Somewhat unfortunately, these efforts are often frustrated by the formation of structures lacking long-range order. Here we show that the rational design of patch shape and symmetry can drive patchy colloids to crystallize in a single, selected morphology by structurally eliminating undesired polymorphs. We provide a proof of this concept through the numerical investigation of triblock Janus colloids. One particular choice of patch symmetry yields, via spontaneous crystallization, a pure tetrastack lattice, a structure with attractive photonic properties, whereas another one results in a colloidal clathrate-like structure, in both cases without any interfering polymorphs. PMID:22828635

  10. Systems vaccinology: Enabling rational vaccine design with systems biological approaches.

    PubMed

    Hagan, Thomas; Nakaya, Helder I; Subramaniam, Shankar; Pulendran, Bali

    2015-09-29

    Vaccines have drastically reduced the mortality and morbidity of many diseases. However, vaccines have historically been developed empirically, and recent development of vaccines against current pandemics such as HIV and malaria has been met with difficulty. The advent of high-throughput technologies, coupled with systems biological methods of data analysis, has enabled researchers to interrogate the entire complement of a variety of molecular components within cells, and characterize the myriad interactions among them in order to model and understand the behavior of the system as a whole. In the context of vaccinology, these tools permit exploration of the molecular mechanisms by which vaccines induce protective immune responses. Here we review the recent advances, challenges, and potential of systems biological approaches in vaccinology. If the challenges facing this developing field can be overcome, systems vaccinology promises to empower the identification of early predictive signatures of vaccine response, as well as novel and robust correlates of protection from infection. Such discoveries, along with the improved understanding of immune responses to vaccination they impart, will play an instrumental role in development of the next generation of rationally designed vaccines. PMID:25858860

  11. A thermostable exo-β-fructosidase immobilised through rational design.

    PubMed

    Martínez, Duniesky; Cutiño-Avila, Bessy; Pérez, Enrique Rosendo; Menéndez, Carmen; Hernández, Lázaro; Del Monte-Martínez, Alberto

    2014-02-15

    Thermotoga maritima exo-β-fructosidase (BfrA) secreted by a recombinant Pichia pastoris strain was optimally immobilised on Glyoxyl-Sepharose CL 4B using the Rational Design of Immobilised Derivatives (RDID) strategy. Covalent attachment of the N-glycosylated BfrA onto the activated support at pH 10 allowed total recovery of the loaded enzyme and its activity. The immobilisation process caused no variation in the catalytic properties of the enzyme and allowed further enhancement of the thermal stability. Complete inversion of cane sugar (2.04 M) in a batch stirred tank reactor at 60 °C was achieved with a productivity of 22.2 g of substrate hydrolysed/gram of biocatalyst/hour. Half-life of the immobilised enzyme of 5 days at 60 °C was determined in a continuously operated fixed-bed column reactor. Our results promote the applicability of the BfrA-immobilised biocatalyst for the complete hydrolysis of concentrated sucrose solutions under industrial conditions, especially at a high reaction temperature. PMID:24128552

  12. Interfacial Templating of Inorganic Nanostructures Using Rationally Designed Peptide Molecules

    NASA Astrophysics Data System (ADS)

    Leon Gibbons, Lorraine

    In nature, biological molecules form interfaces that assemble patterns of chemical functionality with exceptional precision. The role of dynamics during the assembly of biological molecules appears to be important for mineralization processes. The work presented in this dissertation applies model sheet-forming peptides at interfaces to explore the dynamics of assembly in order to template mineral growth. The peptide molecules are rationally designed to have amphiphilic properties and a propensity for sheet-like secondary structure. These designed peptides are deposited at the air/water interface to explore the dynamics of their self-assembly and investigate their 2D order. To characterize the phase behavior, techniques such as Langmuir Blodgett and Brewster Angle Microscopy are used. In addition, we verify the hypothesized sheet-forming propensity using both Circular Dichroism and Attenuated Total Reflection Fourier Transform Infrared Spectroscopy, while the characterization of the inorganic phase is done using Transmission Electron Microscopy, Electron Diffraction, and Atomic Force Microscopy. Thermodynamic analysis of structure formation with increasing pressure allows us to understand the nature of self-assembly with iterative changes in the peptide sequence. Additionally, we look at the dynamics of the self-assembled state, where the organic phase switches between short- and long-range order as a function of surface pressure. We use this model system to explore the influence of electrostatic interactions on self-assembly, and additionally, the influence of short- and long-range order on the nucleation and growth of inorganic material. This is in contrast to a system that starts with a well-ordered preformed template that defines the epitaxial growth of the mineral phase. Two versions of our model peptides are constructed by substituting histidine for glutamic acid in order to nucleate Au nanocrystals in both the short and long range ordered organic matrix, to

  13. Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants

    PubMed Central

    Ben-Yehezkel, Tuval; Atar, Shimshi; Zur, Hadas; Diament, Alon; Goz, Eli; Marx, Tzipy; Cohen, Rafael; Dana, Alexandra; Feldman, Anna; Shapiro, Ehud; Tuller, Tamir

    2015-01-01

    Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5′ transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5′UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5′end can modulate protein levels up to 160%–300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple

  14. Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants.

    PubMed

    Ben-Yehezkel, Tuval; Atar, Shimshi; Zur, Hadas; Diament, Alon; Goz, Eli; Marx, Tzipy; Cohen, Rafael; Dana, Alexandra; Feldman, Anna; Shapiro, Ehud; Tuller, Tamir

    2015-01-01

    Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5' transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5'UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5'end can modulate protein levels up to 160%-300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple rules for

  15. A rationally designed A34R mutant oncolytic poxvirus: improved efficacy in peritoneal carcinomatosis.

    PubMed

    Thirunavukarasu, Pragatheeshwar; Sathaiah, Magesh; Gorry, Michael C; O'Malley, Mark E; Ravindranathan, Roshni; Austin, Frances; Thorne, Steven H; Guo, Zong Sheng; Bartlett, David L

    2013-05-01

    Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. It has been shown that a single point mutation in the A34R gene resulted in the production of more total progeny virus and more extracellular enveloped virus (EEV), a form that can be immune-evasive and with enhanced spread. We have genetically engineered a new oncolytic poxvirus (designated vA34R) by incorporating this mutated A34R gene into a viral backbone (vvDD) which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. These results demonstrate that vA34R gains an enhanced therapeutic index for PC via immune evasion, increased spread, and production of more progeny virus. Thus, vA34R may be a potent oncolytic virus (OV) for patients with PC, even after prior exposure to vaccinia virus (VV). PMID:23439499

  16. Harvesting bioenergy with rationally designed complex functional materials

    NASA Astrophysics Data System (ADS)

    Kuang, Liangju

    A key challenge in renewable energy is to capture, convert and store solar power with earth-abundant materials and environmentally benign technologies. The goal of this thesis is to develop rationally designed complex functional materials for bio-renewable energy applications. On one hand, photoconversion membrane proteins (MPs) are nature's nanoengineering feats for renewable energy management. Harnessing their functions in synthetic systems could help understand, predict, and ultimately control matter and energy at the nanoscale. This is particularly enticing in the post-genome era as recombinant or cell-free expression of many MPs with high yields becomes possible. However, the labile nature of lipid bilayers renders them unsuitable for use in a broad range of engineered systems. A knowledge gap exists about how to design robust synthetic nanomembranes as lipid-bilayer-mimics to support MP functions and how to direct hierarchical MP reconstitution into those membranes to form 2-D or 3-D ordered proteomembrane arrays. Our studies on proteorhodopsin (PR) and bacterial reaction center (BRC), the two light-harvesting MPs, reveal that a charge-interaction-directed reconstitution (CIDR) mechanism induces spontaneous reconstitution of detergent-solubilized MPs into various amphiphilic block copolymer membranes, many of which have far superior stability than lipid bilayers. Our preliminary data also suggest MPs are not enslaved by the biological membranes they derive from; rather, the chemically nonspecific material properties of MP-supporting membranes may act as allosteric regulators. Versatile chemical designs are possible to modulate the conformational energetics of MPs, hence their transport performance in synthetic systems. On the other hand, microalgae are widely regarded as a sustainable feedstock for biofuel production. Microalgae-derived biofuels have not been commercialized yet because current technologies for microalgae dewatering add a huge cost to the

  17. Rational design of single-molecule magnets: a supramolecular approach.

    PubMed

    Glaser, Thorsten

    2011-01-01

    Since the discovery that Mn(12)OAc acts as a single-molecule magnet (SMM), an increasing number of transition metal complexes have been demonstrated to behave as SMMs. The signature of a SMM is a slow relaxation of the magnetization at low temperatures accompanied by a magnetic hysteresis. The origin of SMM behaviour is the existence of an appreciable thermal barrier U for spin-reversal called magnetic anisotropy barrier which is related to the combination of a large total spin ground state (S(t)) and an easy-axis magnetic anisotropy. The extensive research on Mn(12)OAc and other SMMs has established more prerequisites for a rational development of new SMMs besides the high-spin ground state and the magnetic anisotropy: the symmetry should be at least C(3) to minimize the quantum tunneling of the magnetization through the anisotropy barrier but lower than cubic to avoid the cancellation of the local anisotropies upon projection onto the spin ground state. Based on these prerequisites, we have designed the ligand triplesalen which combines the phloroglucinol bridging unit for high spin ground states by the spin-polarization mechanism with a salen-like ligand environment for single-site magnetic anisotropies by a strong tetragonal ligand field. The C(3) symmetric, trinuclear complexes of the triplesalen ligand (talen(t-Bu(2)))(6-) exhibit a strong ligand folding resulting in an overall bowl-shaped molecular structure. This ligand folding preorganizes the axial coordination sites of the metal salen subunits for the complementary binding of three facial nitrogen atoms of a hexacyanometallate unit. This leads to a high driving force for the formation of heptanuclear complexes [M(t)(6)M(c)](n+) by the assembly of three molecular building blocks. Attractive van der Waals interactions of the tert-butyl phenyl units of two triplesalen trinuclear building blocks increase the driving force. In this respect, we have been able to synthesize the isostructural series [Mn(III)(6

  18. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases

    PubMed Central

    Shang, Xun; Marchioni, Fillipo; Sipes, Nisha; Evelyn, Chris R.; Jerabek-Willemsen, Moran; Duhr, Stefan; Seibel, William; Wortman, Matthew; Zheng, Yi

    2012-01-01

    SUMMARY Rho GTPases have been implicated in diverse cellular functions and are potential therapeutic targets. By virtual screening, we have identified a Rho specific inhibitor, Rhosin. Rhosin contains two-aromatic rings tethered by a linker, and it binds to the surface area sandwiching Trp58 of RhoA with a submicromolar Kd and effectively inhibits GEF-catalyzed RhoA activation. In cells Rhosin specifically inhibited RhoA activity and RhoA-mediated cellular function without affecting Cdc42 or Rac1 signaling activities. By suppressing RhoA or RhoC activity Rhosin could inhibit mammary sphere formation by breast cancer cells, suppress invasion of mammary epithelial cells, and induce neurite outgrowth of PC12 cells in synergy with NGF. Thus, the rational designed RhoA subfamily specific small molecule inhibitor is useful for studying the physiological and pathologic roles of Rho GTPase. PMID:22726684

  19. Rational Design of Peptide Vaccines Against Multiple Types of Human Papillomavirus

    PubMed Central

    Dey, Sumanta; De, Antara; Nandy, Ashesh

    2016-01-01

    Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time. PMID:27279731

  20. Rational Design of Peptide Vaccines Against Multiple Types of Human Papillomavirus.

    PubMed

    Dey, Sumanta; De, Antara; Nandy, Ashesh

    2016-01-01

    Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time. PMID:27279731

  1. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1

    PubMed Central

    Evelyn, Chris R.; Duan, Xin; Biesiada, Jacek; Seibel, William L.; Meller, Jaroslaw; Zheng, Yi

    2014-01-01

    Summary Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine-nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, is found to bind to SOS1, competitively suppresses SOS1-Ras interaction, and dose-dependently inhibits SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. PMID:25455859

  2. Rational design of metal-organic frameworks with anticipated porosities and functionalities

    SciTech Connect

    Zhang, MW; Bosch, M; Gentle, T; Zhou, HC

    2014-01-01

    Metal-organic frameworks have emerged as a new category of porous materials that have intriguing structures and diverse applications. Even though the early discovery of new MOFs appears to be serendipitous, much effort has been made to reveal their structure-property relationships for the purpose of rationally designing novel frameworks with expected properties. Until now, much progress has been made to rationalize the design and synthesis of MOFs. This highlight review will outline the recent advances on this topic from both our and other groups and provide a systematic overview of different methods for the rational design of MOFs with desired porosities and functionalities. In this review, we will categorize the recent efforts for rational MOF design into two different approaches: a structural approach and a functional approach.

  3. NCI Designated Cancer Centers

    MedlinePlus

    ... Laboratory for Cancer Research Partners & Collaborators Spotlight on Scientists Research Areas Cancer Biology Cancer Genomics Causes of Cancer ... Cancer Center History Frederick National Laboratory for Cancer Research Partners ... Profiles in Cancer Research Outstanding Investigator Award Recipients ...

  4. Laccase engineering: from rational design to directed evolution.

    PubMed

    Mate, Diana M; Alcalde, Miguel

    2015-01-01

    Laccases are multicopper oxidoreductases considered by many in the biotechonology field as the ultimate "green catalysts". This is mainly due to their broad substrate specificity and relative autonomy (they use molecular oxygen from air as an electron acceptor and they only produce water as by-product), making them suitable for a wide array of applications: biofuel production, bioremediation, organic synthesis, pulp biobleaching, textiles, the beverage and food industries, biosensor and biofuel cell development. Since the beginning of the 21st century, specific features of bacterial and fungal laccases have been exhaustively adapted in order to reach the industrial demands for high catalytic activity and stability in conjunction with reduced production cost. Among the goals established for laccase engineering, heterologous functional expression, improved activity and thermostability, tolerance to non-natural media (organic solvents, ionic liquids, physiological fluids) and resistance to different types of inhibitors are all challenges that have been met, while obtaining a more comprehensive understanding of laccase structure-function relationships. In this review we examine the most significant advances in this exciting research area in which rational, semi-rational and directed evolution approaches have been employed to ultimately convert laccases into high value-added biocatalysts. PMID:25545886

  5. Stereotactic body radiation therapy for prostate cancer: Rational and reasonable.

    PubMed

    Kupelian, Patrick; Mehta, Niraj H; King, Chris; Steinberg, Michael; Finkelstein, Steven E; Fernandez, Eduardo

    2015-01-01

    Stereotactic body radiation therapy (SBRT), a treatment procedure that uses large doses per fraction, is currently being used to treat prostate cancer with external radiation therapy in 4 to 5 treatments. Published series in the clinical use of SBRT in patients with localized prostate cancer demonstrate high efficacy within the available follow-up time periods. Rectal and sexual toxicity profiles have been favorable compared with other radiation techniques and surgery. Urinary toxicity profiles might be more comparable to those observed with brachytherapy, more pronounced in the acute setting. SBRT is technically more challenging, requiring precise geometric targeting with in-room image guidance. The use of large doses per fraction potentially provides unique biological effects on both tumor and normal tissues. Immunologic responses in normal tissues, local stromal microenvironment, and specific antigen-presenting cells induced by such high doses likely contribute to effective tumor kill. Ultimately, SBRT for prostate cancer offers significant logistical advantages, with increased convenience to patients and decreased overall cost to the health care delivery system. PMID:25413392

  6. A rational design change methodology based on experimental and analytical modal analysis

    SciTech Connect

    Weinacht, D.J.; Bennett, J.G.

    1993-08-01

    A design methodology that integrates analytical modeling and experimental characterization is presented. This methodology represents a powerful tool for making rational design decisions and changes. An example of its implementation in the design, analysis, and testing of a precisions machine tool support structure is given.

  7. Platinum anticancer drugs. From serendipity to rational design.

    PubMed

    Monneret, C

    2011-11-01

    The discovery of cis-platin was serendipitous. In 1965, Rosenberg was looking into the effects of an electric field on the growth of Escherichia coli bacteria. He noticed that bacteria ceased to divide when placed in an electric field but what Rosenberg also observed was a 300-fold increase in the size of the bacteria. He attributed this to the fact that somehow the platinum-conducting plates were inducing cell growth but inhibiting cell division. It was later deduced that the platinum species responsible for this was cis-platin. Rosenberg hypothesized that if cis-platin could inhibit bacterial cell division it could also stop tumor cell growth. This conjecture has proven correct and has led to the introduction of cis-platin in cancer therapy. Indeed, in 1978, six years after clinical trials conducted by the NCI and Bristol-Myers-Squibb, the U.S. Food and Drug Administration (FDA) approved cis-platin under the name of Platinol(®) for treating patients with metastatic testicular or ovarian cancer in combination with other drugs but also for treating bladder cancer. Bristol-Myers Squibb also licensed carboplatin, a second-generation platinum drug with fewer side effects, in 1979. Carboplatin entered the U.S. market as Paraplatin(®) in 1989 for initial treatment of advanced ovarian cancer in established combination with other approved chemotherapeutic agents. Numerous platin derivatives have been further developed with more or less success and the third derivative to be approved in 1994 was oxaliplatin under the name of Eloxatin(®). It was the first platin-based drug to be active against metastatic colorectal cancer in combination with fluorouracil and folinic acid. The two others platin-based drugs to be approved were nedaplatin (Aqupla(®)) in Japan and lobaplatin in China, respectively. More recently, a strategy to overcome resistance due to interaction with thiol-containing molecules led to the synthesis of picoplatin in which one of the amines linked to Pt

  8. [Rational approach of antibioprophylaxis: systematic review in ENT cancer surgery].

    PubMed

    Garnier, M; Blayau, C; Fulgencio, J-P; Baujat, B; Arlet, G; Bonnet, F; Quesnel, C

    2013-05-01

    In head and neck cancer surgery antibiotic prophylaxis is effective in reducing the incidence of surgical site infections (SSI). However, controversies between antibiotic prophylaxis and curative antibiotic therapy exist, particularly when complex and decaying surgeries are performed in risky underlying conditions, with a risk of persisting salivary effusion in the postoperative period, or in the case of reconstruction with myo-cutaneous flaps. We have performed a systematic review of the literature according to PRISMA recommendations to answer the following questions: indications for antibiotic prophylaxis and curative antibiotic therapy, optimal duration, and choice of antibiotics for prophylaxis in head and neck cancer surgery. Literature analysis allows to conclude that patients undergoing Altemeier classes 2 and 3 surgical procedures should receive perioperative antibiotic prophylaxis restricted to the first 24 postoperative hours. No benefit has been shown with its extension beyond these 24 hours. The most adapted combinations of antibiotics in this setting are "amoxicillin+clavulanic acid" and "clindamycin+gentamicin". However, the level of evidence regarding the most decaying surgeries with high risk of SSI is low, making it necessary to perform new high-powered randomized trials in these patients. Eventually, it should be noted that antibiotic prophylaxis should be an integral part of SSI preventive measures, including application of hygiene measures, and postoperative monitoring of SSI clinical signs. PMID:23566591

  9. Rational Design of a Zinc Phthalocyanine Binding Protein

    PubMed Central

    Mutter, Andrew C.; Norman, Jessica A.; Tiedemann, Michael T.; Singh, Sunaina; Sha, Sha; Morsi, Sara; Ahmed, Ismail; Stillman, Martin J.; Koder, Ronald L.

    2014-01-01

    Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices. PMID:23827257

  10. Rational design of small molecules as vaccine adjuvants.

    PubMed

    Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

    2014-11-19

    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. PMID:25411473

  11. Rational design of a zinc phthalocyanine binding protein.

    PubMed

    Mutter, Andrew C; Norman, Jessica A; Tiedemann, Michael T; Singh, Sunaina; Sha, Sha; Morsi, Sara; Ahmed, Ismail; Stillman, Martin J; Koder, Ronald L

    2014-02-01

    Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices. PMID:23827257

  12. Rational Design of Molecular Ferroelectric Materials and Nanostructures

    SciTech Connect

    Ducharme, Stephen

    2012-09-25

    The purpose of this project was to gain insight into the properties of molecular ferroelectrics through the detailed study of oligomer analogs of polyvinylidene fluoride (PVDF). By focusing on interactions at both the molecular level and the nanoscale level, we expect to gain improved understanding about the fundamental mechanism of ferroelectricity and its key properties. The research consisted of three complementary components: 1) Rational synthesis of VDF oligomers by Prof. Takacs' group; 2) Detailed structural and electrical studies of thin by Prof. Ducharme's Group; and 3) First-principles computational studies by DOE Lab Partner Dr. Serge Nakhman-son at Argonne National Laboratory. The main results of the work was a detailed understanding of the relationships between the molecular interactions and macroscopic phenomenology of fer-roelectricity VDF oligomers. This is valuable information supporting the development of im-proved electromechanical materials for, e.g., sonar, ultrasonic imaging, artificial muscles, and compliant actuators. Other potential applications include nonvolatile ferroelectric memories, heat-sensing imaging arrays, photovoltaic devices, and functional biomimetic materials. The pro-ject contributed to the training and professional development of undergraduate students and graduate students, post-doctoral assistants, and a high-school teacher. Project personnel took part in several outreach and education activities each year.

  13. Construction of a rationally designed antibody platform for sequencing-assisted selection.

    PubMed

    Larman, H Benjamin; Xu, George Jing; Pavlova, Natalya N; Elledge, Stephen J

    2012-11-01

    Antibody discovery platforms have become an important source of both therapeutic biomolecules and research reagents. Massively parallel DNA sequencing can be used to assist antibody selection by comprehensively monitoring libraries during selection, thus greatly expanding the power of these systems. We have therefore constructed a rationally designed, fully defined single-chain variable fragment (scFv) library and analysis platform optimized for analysis with short-read deep sequencing. Sequence-defined oligonucleotide libraries encoding three complementarity-determining regions (L3 from the light chain, H2 and H3 from the heavy chain) were synthesized on a programmable microarray and combinatorially cloned into a single scFv framework for molecular display. Our unique complementarity-determining region sequence design optimizes for protein binding by utilizing a hidden Markov model that was trained on all antibody-antigen cocrystal structures in the Protein Data Bank. The resultant ~10(12)-member library was produced in ribosome-display format, and comprehensively analyzed over four rounds of antigen selections by multiplex paired-end Illumina sequencing. The hidden Markov model scFv library generated multiple binders against an emerging cancer antigen and is the basis for a next-generation antibody production platform. PMID:23064642

  14. Integrating research and development: the emergence of rational drug design in the pharmaceutical industry.

    PubMed

    Adam, Matthias

    2005-09-01

    Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. PMID:16137601

  15. Design of Catalytic Peptides and Proteins Through Rational and Combinatorial Approaches.

    PubMed

    Maeda, Yoshiaki; Makhlynets, Olga V; Matsui, Hiroshi; Korendovych, Ivan V

    2016-07-11

    This review focuses on recent progress in noncomputational methods to introduce catalytic function into proteins, peptides, and peptide assemblies. We discuss various approaches to creating catalytic activity and classification of noncomputational methods into rational and combinatorial classes. The section on rational design covers recent progress in the development of short peptides and oligomeric peptide assemblies for various natural and unnatural reactions. The section on combinatorial design describes recent advances in the discovery of catalytic peptides. We present the future prospects of these and other new approaches in a broader context, including implications for functional material design. PMID:27022702

  16. Rational design of orthogonal libraries of protein coding genes.

    PubMed

    Ryan, Daniel; Papamichail, Dimitris

    2013-05-17

    Array-based oligonucleotide synthesis technologies provide access to thousands of custom-designed sequence variants at low cost. Large-scale synthesis and high-throughput assays have become valuable experimental tools to study in detail the interplay between sequence and function. We have developed a methodology and corresponding algorithms for the design of diverse protein coding gene libraries, to exploit the potential of multiplex synthesis and help elucidate the effects of codon utilization and other factors in gene expression. Using our algorithm, we have computationally designed gene libraries with hundreds to thousands of orthogonal codon usage variants, uniformly exploring the design space of codon utilization, while demanding only a small fraction of the synthesis cost that would be required if these variants were synthesized independently. PMID:23654273

  17. Glycoscience -- a new frontier in rational drug design.

    PubMed

    Gornik, Olga; Dumić, Jerka; Flogel, Mirna; Lauc, Gordan

    2006-03-01

    Glycans are the most abundant and most diverse biopolymers in nature. Because of their highly specific interactions with physiological receptors, they participate in many crucial biological processes. All these processes are potential targets for therapeutic intervention, and carbohydrate-based drugs are rapidly being taken up by the modern biotechnology and pharmaceutical industry. Recent developments in the field of glycobiology have overcome the problem of glycan analysis and synthesis; and many compounds based on carbohydrates are now in various stages of clinical trials. This article presents glycoproteins in a new light, as an important biopharmaceutical target, giving an overview of their potential use as therapeutic glycoproteins and proteoglycans, inflammation blockers, cancer therapeutics and vaccines, inhibitors of pathogenic microbes, viral inhibitors and potential aids in the treatment of lysosomal diseases, neurological diseases and transplantation rejection. PMID:16613732

  18. Rational design of mirror-like peptides with alanine regulation.

    PubMed

    Li, Weizhong; Tan, Tingting; Xu, Wei; Xu, Lin; Dong, Na; Ma, Deying; Shan, Anshan

    2016-02-01

    To generate effective antimicrobial peptides (AMPs) with good antimicrobial activities and cell selectivity, many synthetic strategies have been implemented to facilitate the development of AMPs. However, these synthetic strategies represent only a small proportion of the methods used for the development of AMPs and are not optimal with the requirements needed for the design of AMPs. In this investigation, we designed a mirror-like structure with a lower charge and a higher number of hydrophobic amino acids. The amino acid sequence of the designed mirror-like peptides was XXYXXXYXXXYXX [X represents L (Leu) and/or A (Ala); Y represents K (Lys)]. These mirror-like peptides displayed antimicrobial activity against both Gram-positive and Gram-negative bacteria. Hemolysis activity and cytotoxicity, detected by using human red blood cells (hRBCs) and human embryonic kidney cells (HEK293), respectively, demonstrated that the frequency of Ala residues in this structure had a regulatory effect on the high hydrophobic region. In particular, KL4A6 showed a greater antimicrobial potency than the other three mirror-like peptides, folded into an α-helical structure, and displayed the highest therapeutic index, suggesting its good cell selectivity. Observations from fluorescence spectroscopy, flow cytometry, and electron microscopy experiments indicated that KL4A6 exhibited good membrane penetration potential by inducing membrane blebbing, disruption and lysis. Therefore, generating mirror-like peptides is a promising strategy for designing effective AMPs with regions of high hydrophobicity. PMID:26385363

  19. Rational design of an organometallic glutathione transferase inhibitor

    SciTech Connect

    Ang, W.H.; Parker, L.J.; De Luca, A.; Juillerat-Jeanneret, L.; Morton, C.J.; LoBello, M.; Parker, M.W.; Dyson, P.J.

    2010-08-17

    A hybrid organic-inorganic (organometallic) inhibitor was designed to target glutathione transferases. The metal center is used to direct protein binding, while the organic moiety acts as the active-site inhibitor. The mechanism of inhibition was studied using a range of biophysical and biochemical methods.

  20. Rational Design of Pathogen-Mimicking Amphiphilic Materials as Nanoadjuvants

    NASA Astrophysics Data System (ADS)

    Ulery, Bret D.; Petersen, Latrisha K.; Phanse, Yashdeep; Kong, Chang Sun; Broderick, Scott R.; Kumar, Devender; Ramer-Tait, Amanda E.; Carrillo-Conde, Brenda; Rajan, Krishna; Wannemuehler, Michael J.; Bellaire, Bryan H.; Metzger, Dennis W.; Narasimhan, Balaji

    2011-12-01

    An opportunity exists today for cross-cutting research utilizing advances in materials science, immunology, microbial pathogenesis, and computational analysis to effectively design the next generation of adjuvants and vaccines. This study integrates these advances into a bottom-up approach for the molecular design of nanoadjuvants capable of mimicking the immune response induced by a natural infection but without the toxic side effects. Biodegradable amphiphilic polyanhydrides possess the unique ability to mimic pathogens and pathogen associated molecular patterns with respect to persisting within and activating immune cells, respectively. The molecular properties responsible for the pathogen-mimicking abilities of these materials have been identified. The value of using polyanhydride nanovaccines was demonstrated by the induction of long-lived protection against a lethal challenge of Yersinia pestis following a single administration ten months earlier. This approach has the tantalizing potential to catalyze the development of next generation vaccines against diseases caused by emerging and re-emerging pathogens.

  1. Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

    PubMed

    Le Chapelain, Camille; Groll, Michael

    2016-05-23

    One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle. PMID:27079849

  2. On the rational design of compressible flow ejectors

    NASA Technical Reports Server (NTRS)

    Ortwerth, P. J.

    1979-01-01

    A fluid mechanics review of chemical laser ejectors is presented. The characteristics of ejectors with single and multiple driver nozzles are discussed. Methods to compute an optimized performance map in which secondary Mach number and performance are computed versus mass ratio, to compute the flow distortion at each optimized condition, and to determine the thrust area for the design point to match diffuser impedence are examined.

  3. Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

    PubMed Central

    Onuoha, Shimobi C.; Ferrari, Mathieu; Sblattero, Daniele

    2015-01-01

    Objective Biologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. Methods Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. Results Intact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules. Conclusion The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of

  4. Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics.

    PubMed

    Low, Kristin E; Ler, Spencer; Chen, Kevin J; Campbell, Robert L; Hickey, Jennifer L; Tan, Joanne; Scully, Conor C G; Davies, Peter L; Yudin, Andrei K; Zaretsky, Serge

    2016-06-01

    Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a β-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor. PMID:27148623

  5. Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity.

    PubMed

    Allemann, Oliver; Brutsch, Manuela; Lukesh, John C; Brody, Daniel M; Boger, Dale L

    2016-07-13

    Many natural products, including vinblastine, have not been easily subjected to simplifications in their structures by synthetic means or modifications by late-stage semisynthetic derivatization in ways that enhance their biological potency. Herein, we detail a synthetic vinblastine that incorporates added benign complexity (ABC), which improves activity 10-fold, and is now accessible as a result of advances in the total synthesis of the natural product. The compound incorporates designed added molecular complexity but no new functional groups and maintains all existing structural and conformational features of the natural product. It constitutes a member of an analogue class presently inaccessible by semisynthetic derivatization of the natural product, by its late-stage functionalization, or by biosynthetic means. Rather, it was accessed by synthetic means, using an appropriately modified powerful penultimate single-step vindoline-catharanthine coupling strategy that proceeds with a higher diastereoselectivity than found for the natural product itself. PMID:27356080

  6. Rational design of potent human transthyretin amyloid disease inhibitors.

    PubMed

    Klabunde, T; Petrassi, H M; Oza, V B; Raman, P; Kelly, J W; Sacchettini, J C

    2000-04-01

    The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases. PMID:10742177

  7. Rational design of a split-Cas9 enzyme complex

    PubMed Central

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-01-01

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. Although the lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications. PMID:25713377

  8. Rational medium design for Bordetella pertussis: basic metabolism.

    PubMed

    Thalen, M; van den IJssel, J; Jiskoot, W; Zomer, B; Roholl, P; de Gooijer, C; Beuvery, C; Tramper, J

    1999-10-01

    In current Bordetella pertussis media ammonium accumulates because of an imbalance in the nitrogen:carbon ratio of the substrates used, which is one of the factors limiting cell density in fed-batch cultures. The aim of this study was to map B. pertussis catabolic and anabolic capabilities, in order to design a medium that avoids ammonium accumulation, while substrates are metabolised completely. Besides the known dysfunctional glycolysis, B. pertussis also possessed a partially dysfunctional citric-acid cycle. Although ammonium accumulation was avoided by adding various carbon sources to medium with glutamate, nuclear magnetic resonance (NMR) showed excretion of acetate, acetoacetate and beta-hydroxy-butyrate, thereby reducing the biomass yield. Acetoacetate and beta-hydroxy-butyrate were also formed in Verwey, B2 and modified Stainer-Scholte medium. Electron microscopy in combination with NMR showed that cells early on in these cultures contained poly-hydroxy-butyrate (PHB) globules, which disappeared later during the culture, coinciding with the appearance of beta-hydroxy-butyrate and/or acetoacetate. No globules nor metabolite excretion was detected when lactate in combination with glutamate were used as substrates. Thus, metabolite excretion and ammonium accumulation were avoided, while the yield of 8.8 g C-mol-1 compared favourably with literature values, averaging 6.5 g C-mol-1. Optimisation of this medium for pertussis toxin production will be reported in a separate article. PMID:10553654

  9. Rational design of a split-Cas9 enzyme complex

    DOE PAGESBeta

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-02-23

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. The lobes do not interactmore » on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications.« less

  10. Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

    2015-01-01

    Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.

  11. Resistance identification and rational process design in Capacitive Deionization.

    PubMed

    Dykstra, J E; Zhao, R; Biesheuvel, P M; van der Wal, A

    2016-01-01

    Capacitive Deionization (CDI) is an electrochemical method for water desalination employing porous carbon electrodes. To enhance the performance of CDI, identification of electronic and ionic resistances in the CDI cell is important. In this work, we outline a method to identify these resistances. We illustrate our method by calculating the resistances in a CDI cell with membranes (MCDI) and by using this knowledge to improve the cell design. To identify the resistances, we derive a full-scale MCDI model. This model is validated against experimental data and used to calculate the ionic resistances across the MCDI cell. We present a novel way to measure the electronic resistances in a CDI cell, as well as the spacer channel thickness and porosity after assembly of the MCDI cell. We identify that for inflow salt concentrations of 20 mM the resistance is mainly located in the spacer channel and the external electrical circuit, not in the electrodes. Based on these findings, we show that the carbon electrode thickness can be increased without significantly increasing the energy consumption per mol salt removed, which has the advantage that the desalination time can be lengthened significantly. PMID:26512814

  12. Rational design of the car hearth of a tunnel furnace

    SciTech Connect

    Kryzhanovskii, K.S.; Chernyi, V.I.; Dunaevskii, O.M.; Mokhort, V.N.; Sedoi, N.I.

    1985-09-01

    In tunnel furnaces the heat losses into the environment amount to 15-20% of the burnt-fuel heat. The heat is essentially lost through the car (carrier) hearth into the corridor of the furnace bottom. A light-weight car has been designed that is thermally insulated using a high-alumina kaolin fiber of the VGR-130 mark. The car-hearth weight was reduced by 1.5 times by using a light-weight fireclay and incorporating an air space within the hearth. Using the method of finite differences, the authors determined the dynamics of temperature field variation along the height of the car-hearth before and after its reconstruction as applied to the firing parameters of the products in the tunnel furnace. The results of the determinations are presented. An additional thermal insulation of the car hearth using a 15-20 mm thick high-alumina kaolin fiber also makes it possible to reduce the heat losses in the furnace-bottom corridor by 30-40%, and thereby, to decrease the maximum temperature in the corridor from 90 to 60 degrees C, which significantly improves energy efficiency.

  13. Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

    PubMed Central

    Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

    2015-01-01

    Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy. PMID:25633824

  14. Rational design of bleachable nonchemically amplified DUV photoactive compounds

    NASA Astrophysics Data System (ADS)

    Rathsack, Benjamen M.; Tattersall, Peter I.; Tabery, Cyrus E.; Lou, Kathleen; Stachowiak, Timothy B.; Medeiros, David R.; Albelo, Jeff A.; Pirogovsky, Peter Y.; McKean, Dennis R.; Willson, C. Grant

    2001-08-01

    Photoactive compounds have been designed, synthesized and characterized for deep ultraviolet non-chemically amplified resist applications. These resist materials may have potential use in next generation 257nm mask fabrication. Mask fabrication requires stringent linewidth specifications over long post-coat and post-exposure bake delays. Lithography simulation and imaging experiments have been done to determine the lithographic performance of resists formulated with these new photoactive compounds. Previously studied chromophores, 7 substituted 3-diazo 4- hydroxycoumarin and N-substituted 3-diazo-2, 4-piperidione, both have the transparency, bleaching and exposure rate kinetics in the DUV that are analogous to those exhibited by the diazonaphthoquinone chromophore at 365nm. The sulfonate linkages attached to these photoactive compounds provide dissolution rate inhibition of novolak that is very similar to the diazonaphthoquinone-sulfonates. The trifunctional diazopiperidione that incorporates three sulfonate linkages provides more efficient inhibition per chromophore than the corresponding bisfunctional photoactive compound. The diazocoumarin based novolak resist demonstrates image reversal (negative tone) with the use of a post-exposure bake. The post-exposure bake causes the exposed photoactive compound to decarboxylate, which dramatically reduces its solubility in aqueous base. The trifunctional diazopiperidione provides the best overall imaging results due to almost complete bleaching and high contrast.

  15. Rational design of a split-Cas9 enzyme complex

    SciTech Connect

    Wright, Addison V.; Sternberg, Samuel H.; Taylor, David W.; Staahl, Brett T.; Bardales, Jorge A.; Kornfeld, Jack E.; Doudna, Jennifer A.

    2015-02-23

    Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. The lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications.

  16. Rational method for design of wick drain systems

    NASA Astrophysics Data System (ADS)

    Landau, Richard E.

    the time to complete 90% of primary consolidation in the field. Procedures are described to determine the field induced pore pressure profile needed to apply the empirical relationship in design.

  17. Testing the limits of rational design by engineering pH sensitivity into membrane-active peptides.

    PubMed

    Wiedman, Gregory; Wimley, William C; Hristova, Kalina

    2015-04-01

    In this work, we sought to rationally design membrane-active peptides that are triggered by low pH to form macromolecular-sized pores in lipid bilayers. Such peptides could have broad utility in biotechnology and in nanomedicine as cancer therapeutics or drug delivery vehicles that promote release of macromolecules from endosomes. Our approach to rational design was to combine the properties of a pH-independent peptide, MelP5, which forms large pores allowing passage of macromolecules, with the properties of two pH-dependent membrane-active peptides, pHlip and GALA. We created two hybrid sequences, MelP5_Δ4 and MelP5_Δ6, by using the distribution of acidic residues on pHlip and GALA as a guide to insert acidic amino acids into the amphipathic helix of MelP5. We show that the new peptides bind to lipid bilayers and acquire secondary structure in a pH-dependent manner. The peptides also destabilize bilayers in a pH-dependent manner, such that lipid vesicles release the small molecules ANTS/DPX at low pH only. Thus, we were successful in designing pH-triggered pore-forming peptides. However, no macromolecular release was observed under any conditions. Therefore, we abolished the unique macromolecular poration properties of MelP5 by introducing pH sensitivity into its sequence. We conclude that the properties of pHlip, GALA, and MelP5 are additive, but only partially so. We propose that this lack of additivity is a limitation in the rational design of novel membrane-active peptides, and that high-throughput approaches to discovery will be critical for continued progress in the field. PMID:25572997

  18. Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes

    PubMed Central

    Pena, Darlene Aparecida; Andrade, Victor Piana de; Silva, Gabriela Ávila Fernandes; Neves, José Ivanildo; Oliveira, Paulo Sergio Lopes de; Alves, Maria Julia Manso; Devi, Lakshmi A.; Schechtman, Deborah

    2016-01-01

    Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules. PMID:26911897

  19. Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes.

    PubMed

    Pena, Darlene Aparecida; Andrade, Victor Piana de; Silva, Gabriela Ávila Fernandes; Neves, José Ivanildo; Oliveira, Paulo Sergio Lopes de; Alves, Maria Julia Manso; Devi, Lakshmi A; Schechtman, Deborah

    2016-01-01

    Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules. PMID:26911897

  20. Rational design of a comprehensive cancer therapy platform using temperature-sensitive polymer grafted hollow gold nanospheres: simultaneous chemo/photothermal/photodynamic therapy triggered by a 650 nm laser with enhanced anti-tumor efficacy.

    PubMed

    Deng, Xiaoran; Chen, Yinyin; Cheng, Ziyong; Deng, Kerong; Ma, Ping'an; Hou, Zhiyao; Liu, Bei; Huang, Shanshan; Jin, Dayong; Lin, Jun

    2016-03-28

    Combining multi-model treatments within one single system has attracted great interest for the purpose of synergistic therapy. In this paper, hollow gold nanospheres (HAuNs) coated with a temperature-sensitive polymer, poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy)ethyl methacrylate) (p(OEGMA-co-MEMA)), co-loaded with DOX and a photosensitizer Chlorin e6 (Ce6) were successfully synthesized. As high as 58% DOX and 6% Ce6 by weight could be loaded onto the HAuNs-p(OEGMA-co-MEMA) nanocomposites. The grafting polymer brushes outside the HAuNs play the role of "gate molecules" for controlled drug release by 650 nm laser radiation owing to the temperature-sensitive property of the polymer and the photothermal effect of HAuNs. The HAuNs-p(OEGMA-co-MEMA)-Ce6-DOX nanocomposites with 650 nm laser radiation show effective inhibition of cancer cells in vitro and enhanced anti-tumor efficacy in vivo. In contrast, control groups without laser radiation show little cytotoxicity. The nanocomposite demonstrates a way of "killing three birds with one stone", that is, chemotherapy, photothermal and photodynamic therapy are triggered simultaneously by the 650 nm laser stimulation. Therefore, the nanocomposites show the great advantages of multi-modal synergistic effects for cancer therapy by a remote-controlled laser stimulus. PMID:26956400

  1. Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

    PubMed Central

    Blakeley, Jaishri; Portnow, Jana

    2014-01-01

    Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID:20969450

  2. Rational design of a comprehensive cancer therapy platform using temperature-sensitive polymer grafted hollow gold nanospheres: simultaneous chemo/photothermal/photodynamic therapy triggered by a 650 nm laser with enhanced anti-tumor efficacy

    NASA Astrophysics Data System (ADS)

    Deng, Xiaoran; Chen, Yinyin; Cheng, Ziyong; Deng, Kerong; Ma, Ping'an; Hou, Zhiyao; Liu, Bei; Huang, Shanshan; Jin, Dayong; Lin, Jun

    2016-03-01

    Combining multi-model treatments within one single system has attracted great interest for the purpose of synergistic therapy. In this paper, hollow gold nanospheres (HAuNs) coated with a temperature-sensitive polymer, poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy)ethyl methacrylate) (p(OEGMA-co-MEMA)), co-loaded with DOX and a photosensitizer Chlorin e6 (Ce6) were successfully synthesized. As high as 58% DOX and 6% Ce6 by weight could be loaded onto the HAuNs-p(OEGMA-co-MEMA) nanocomposites. The grafting polymer brushes outside the HAuNs play the role of ``gate molecules'' for controlled drug release by 650 nm laser radiation owing to the temperature-sensitive property of the polymer and the photothermal effect of HAuNs. The HAuNs-p(OEGMA-co-MEMA)-Ce6-DOX nanocomposites with 650 nm laser radiation show effective inhibition of cancer cells in vitro and enhanced anti-tumor efficacy in vivo. In contrast, control groups without laser radiation show little cytotoxicity. The nanocomposite demonstrates a way of ``killing three birds with one stone'', that is, chemotherapy, photothermal and photodynamic therapy are triggered simultaneously by the 650 nm laser stimulation. Therefore, the nanocomposites show the great advantages of multi-modal synergistic effects for cancer therapy by a remote-controlled laser stimulus.Combining multi-model treatments within one single system has attracted great interest for the purpose of synergistic therapy. In this paper, hollow gold nanospheres (HAuNs) coated with a temperature-sensitive polymer, poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy)ethyl methacrylate) (p(OEGMA-co-MEMA)), co-loaded with DOX and a photosensitizer Chlorin e6 (Ce6) were successfully synthesized. As high as 58% DOX and 6% Ce6 by weight could be loaded onto the HAuNs-p(OEGMA-co-MEMA) nanocomposites. The grafting polymer brushes outside the HAuNs play the role of ``gate molecules'' for controlled drug release by 650 nm laser radiation

  3. Rational design and optimization of fed-batch and continuous fermentations.

    PubMed

    Zhang, Wenhui; Inan, Mehmet; Meagher, Michael M

    2007-01-01

    This chapter provides rational approaches to design and optimize fed-batch and continuous fermentations of both Mut+ and Muts (methanol utilization plus and slow) Pichia pastoris strains. The methods are described in detail for glycerol batch, glycerol fed-batch, transition, and methanol fed-batch/mixed feed/ continuous stirred tank reactor (CSTR) phases of the process based on glycerol and methanol consumption models. Cell density, broth volume, substrate feed rate, and the length of each phase are rationally designed to conduct runs with selected parameters for optimizing a process. The optimization is anchored by the impact of a specific growth rate/dilution time (for CSTRs) on productivity. Equations for simulation of a process with optimal parameters are derived for an optimal process design. This protocol can be used as a practical manual for process development of a P. pastoris recombinant fermentation, and also as a reference for fermentation of other microorganisms. PMID:17951634

  4. Rational design of metal oxide nanocomposite anodes for advanced lithium ion batteries

    NASA Astrophysics Data System (ADS)

    Li, Yong; Yu, Shenglan; Yuan, Tianzhi; Yan, Mi; Jiang, Yinzhu

    2015-05-01

    Metal-oxide anodes represent a significant future direction for advanced lithium ion batteries. However, their practical applications are still seriously hampered by electrode disintegration and capacity fading during cycling. Here, we report a rational design of 3D-staggered metal-oxide nanocomposite electrode directly fabricated by pulsed spray evaporation chemical vapor deposition, where various oxide nanocomponents are in a staggered distribution uniformly along three dimensions and across the whole electrode. Such a special design of nanoarchitecture combines the advantages of nanoscale materials in volume change and Li+/electron conduction as well as uniformly staggered and compact structure in atom migration during lithiation/delithiation, which exhibits high specific capacity, good cycling stability and excellent rate capability. The rational design of metal-oxide nanocomposite electrode opens up new possibilities for high performance lithium ion batteries.

  5. Rational design of new electrolyte materials for electrochemical double layer capacitors

    NASA Astrophysics Data System (ADS)

    Schütter, Christoph; Husch, Tamara; Viswanathan, Venkatasubramanian; Passerini, Stefano; Balducci, Andrea; Korth, Martin

    2016-09-01

    The development of new electrolytes is a centerpiece of many strategies to improve electrochemical double layer capacitor (EDLC) devices. We present here a computational screening-based rational design approach to find new electrolyte materials. As an example application, the known chemical space of almost 70 million compounds is investigated in search of electrochemically more stable solvents. Cyano esters are identified as especially promising new compound class. Theoretical predictions are validated with subsequent experimental studies on a selected case. These studies show that based on theoretical predictions only, a previously untested, but very well performing compound class was identified. We thus find that our rational design strategy is indeed able to successfully identify completely new materials with substantially improved properties.

  6. Controlling the Spin Texture of Topological Insulators by Rational Design of Organic Molecules.

    PubMed

    Jakobs, Sebastian; Narayan, Awadhesh; Stadtmüller, Benjamin; Droghetti, Andrea; Rungger, Ivan; Hor, Yew S; Klyatskaya, Svetlana; Jungkenn, Dominik; Stöckl, Johannes; Laux, Martin; Monti, Oliver L A; Aeschlimann, Martin; Cava, Robert J; Ruben, Mario; Mathias, Stefan; Sanvito, Stefano; Cinchetti, Mirko

    2015-09-01

    We present a rational design approach to customize the spin texture of surface states of a topological insulator. This approach relies on the extreme multifunctionality of organic molecules that are used to functionalize the surface of the prototypical topological insulator (TI) Bi2Se3. For the rational design we use theoretical calculations to guide the choice and chemical synthesis of appropriate molecules that customize the spin texture of Bi2Se3. The theoretical predictions are then verified in angular-resolved photoemission experiments. We show that, by tuning the strength of molecule-TI interaction, the surface of the TI can be passivated, the Dirac point can energetically be shifted at will, and Rashba-split quantum-well interface states can be created. These tailored interface properties-passivation, spin-texture tuning, and creation of hybrid interface states-lay a solid foundation for interface-assisted molecular spintronics in spin-textured materials. PMID:26262825

  7. Rationally designed multifunctional plasmonic nanostructures for surface-enhanced Raman spectroscopy: a review

    NASA Astrophysics Data System (ADS)

    Xie, Wei; Schlücker, Sebastian

    2014-11-01

    Rationally designed multifunctional plasmonic nanostructures efficiently integrate two or more functionalities into a single entity, for example, with both plasmonic and catalytic activity. This review article is focused on their synthesis and use in surface-enhanced Raman scattering (SERS) as a molecular spectroscopic technique with high sensitivity, fingerprint specificity, and surface selectivity. After a short tutorial on the fundamentals of Raman scattering and SERS in particular, applications ranging from chemistry (heterogeneous catalysis) to biology and medicine (diagnostics/imaging, therapy) are summarized.

  8. Rational design and synthesis of a porous, task-specific polycarbazole for efficient CO2 capture.

    PubMed

    Jin, Tian; Xiong, Yan; Zhu, Xiang; Tian, Ziqi; Tao, Duan-Jian; Hu, Jun; Jiang, De-en; Wang, Hualin; Liu, Honglai; Dai, Sheng

    2016-03-25

    We present a rational design and synthesis of a novel porous pyridine-functionalized polycarbazole for efficient CO2 capture based on the density functional theory calculations. The task-specific polymer, generated through a one-step FeCl3-catalyzed oxidative coupling reaction, exhibits a superior CO2 uptake at 1.0 bar and 273 K (5.57 mmol g(-1)). PMID:26864392

  9. Rational designed bipolar, conjugated polymer-DNA composite beacon for the sensitive detection of proteins and ions.

    PubMed

    Jia, Yongmei; Zuo, Xiaolei; Lou, Xiaoding; Miao, Mao; Cheng, Yong; Min, Xuehong; Li, Xinchun; Xia, Fan

    2015-04-01

    Nature owns remarkable capabilities in sensing target molecules, while the artificial biosensor lags far behind nature. Inspired by nature, we devise a new sensing platform that can specifically bind the molecules and synchronously initiate a specific signal response. We rationally designed a type of bipolar probe that is comprised of a hydrophilic DNA part and a hydrophobic conjugated polymer (CP) unit. In aqueous solution, they can form micelles with a hydrophobic CP core and a hydrophilic DNA shell. The aggregation-caused quenching suppresses the fluorescence of CP. Adding telomerase, the hydropathical profile of the bipolar probes is drastically regulated that results in the collapse of micelles and liberates fluorescence simultaneously. The probe has been used in both mimic systems and real urine samples (38 samples). We achieve sensitive and specific detection of telomerase and obtain clearly classification for normal people and cancer patients. It can also be used in a signal off sensor that is used to detect mercury ions. PMID:25694029

  10. Rational peptide design for functional materials via molecular self-assembly

    NASA Astrophysics Data System (ADS)

    Rajagopal, Karthikan

    Supra-molecular self-assembly of rationally designed peptides is a promising approach to construct functional materials. This thesis specifically focuses on hydrogels, an important class of materials with potential for applications in tissue engineering, drug delivery and micro-fluidic systems. The objective is to design short peptides that would specifically adopt a stimulus dependent conformation that is strongly amenable to self-assembly resulting in material formation. With this concept the rational design of a 20 amino acid peptide (MAX1) that folds into an amphiphilic beta-hairpin structure and then self-assembles to form a rigid hydrogel under alkaline conditions is presented. The molecular level conformation of MAX1 was characterized using circular dichroism and FTIR spectroscopies. The mesoscale structure of the hydrogel assessed using confocal and transmission electron micron microscopies and neutron scattering techniques shows that peptide self-assembly results in the formation of fibrils that are homogeneously 3 nm in diameter. The mechanical properties of the hydrogel probed using oscillatory rheology shows that MAX1 forms a stiff hydrogel. Since the self-assembly process is coupled to the intra-molecularly folded state of the peptide, stimulus responsiveness can be specifically engineered into the sequence by rational design. This was demonstrated in the design of peptides that form hydrogels in response to a specific stimulus such as temperature, pH or ionic strength. The significance of peptide design in the context of self-assembly and its relationship to the nanostructure was studied by designing a series of peptides derived from MAX1. Evolving from these studies is an understanding of the relationship between molecular level peptide structure and the nanoscale supra-molecular morphology. Based on this, it has been shown that alternate morphologies distinct from those observed with the gel forming peptides, such as non-twisting laminates or tube

  11. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    PubMed Central

    Lau, Vincent Wing-hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant ‘defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  12. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites

    NASA Astrophysics Data System (ADS)

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B.; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V.

    2016-07-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant `defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts.

  13. Rational design of carbon nitride photocatalysts by identification of cyanamide defects as catalytically relevant sites.

    PubMed

    Lau, Vincent Wing-Hei; Moudrakovski, Igor; Botari, Tiago; Weinberger, Simon; Mesch, Maria B; Duppel, Viola; Senker, Jürgen; Blum, Volker; Lotsch, Bettina V

    2016-01-01

    The heptazine-based polymer melon (also known as graphitic carbon nitride, g-C3N4) is a promising photocatalyst for hydrogen evolution. Nonetheless, attempts to improve its inherently low activity are rarely based on rational approaches because of a lack of fundamental understanding of its mechanistic operation. Here we employ molecular heptazine-based model catalysts to identify the cyanamide moiety as a photocatalytically relevant 'defect'. We exploit this knowledge for the rational design of a carbon nitride polymer populated with cyanamide groups, yielding a material with 12 and 16 times the hydrogen evolution rate and apparent quantum efficiency (400 nm), respectively, compared with the unmodified melon. Computational modelling and material characterization suggest that this moiety improves coordination (and, in turn, charge transfer kinetics) to the platinum co-catalyst and enhances the separation of the photogenerated charge carriers. The demonstrated knowledge transfer for rational catalyst design presented here provides the conceptual framework for engineering high-performance heptazine-based photocatalysts. PMID:27387536

  14. Inventing and improving ribozyme function: rational design versus iterative selection methods

    NASA Technical Reports Server (NTRS)

    Breaker, R. R.; Joyce, G. F.

    1994-01-01

    Two major strategies for generating novel biological catalysts exist. One relies on our knowledge of biopolymer structure and function to aid in the 'rational design' of new enzymes. The other, often called 'irrational design', aims to generate new catalysts, in the absence of detailed physicochemical knowledge, by using selection methods to search a library of molecules for functional variants. Both strategies have been applied, with considerable success, to the remodeling of existing ribozymes and the development of ribozymes with novel catalytic function. The two strategies are by no means mutually exclusive, and are best applied in a complementary fashion to obtain ribozymes with the desired catalytic properties.

  15. Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.

    PubMed

    Ehrt, Christiane; Brinkjost, Tobias; Koch, Oliver

    2016-05-12

    Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct selectivity patterns and the prediction of possible off-target effects. The identification of similarities between binding sites of various proteins is a useful approach to cope with those challenges. The main scope of this perspective is to describe applications of different protein binding site comparison approaches to outline their applicability and impact on molecular design. The article deals with various substantial application domains and provides some outstanding examples to show how various binding site comparison methods can be applied to promote in silico drug design workflows. In addition, we will also briefly introduce the fundamental principles of different protein binding site comparison methods. PMID:27046190

  16. Rational design and application of a redox-active, photoresponsive, discrete metallogelator.

    PubMed

    Afrasiabi, Rouzbeh; Kraatz, Heinz-Bernhard

    2015-05-18

    A photoresponsive discrete metallogelator was rationally designed by incorporating a photochromic azobenzene subunit in the structure of a redox-active ferrocene-peptide conjugate. The target molecule was purposefully equipped with a dipeptide unit capable of self-assembly in response to sonication. The designed molecule was shown to undergo supramolecular self-assembly and achieve organogelation in response to ultrasound, light, heat, and redox signals. The sol-gel phase transition of the designed gelator was found to be sensitive to a plethora of input stimuli, allowing the application of the sol-gel transition behavior in basic logic gate operations. A gel-based NOT logic gate operation was realized when the redox-active property of the organogel was examined by using different oxidizing agents. The smart response of the gelator was further exploited in designing XOR operations under oxidizing or non-oxidizing conditions. PMID:25827318

  17. Novel ligands rationally designed for characterizing I2-imidazoline binding sites nature and functions.

    PubMed

    Gentili, Francesco; Cardinaletti, Claudia; Vesprini, Cristian; Ghelfi, Francesca; Farande, Aniket; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Mattioli, Laura; Perfumi, Marina; Hudson, Alan; Pigini, Maria

    2008-08-28

    The study of two series of 2-aryl-ethylen-imidazolines 3-7 and 8-12 inspired by I2-IBS ligands phenyzoline (1) and diphenyzoline (2), respectively, confirmed the interesting "positive" or "negative" morphine analgesia modulation displayed by their corresponding leads and demonstrated that these effects might be correlated with morphine tolerance and dependence, respectively. By comparative examination of rationally designed compounds, some analogies between binding site cavity of I2-IBS proteins and alpha 2C-adrenoreceptor emerged. PMID:18661965

  18. Rationally designed multifunctional plasmonic nanostructures for surface-enhanced Raman spectroscopy: a review.

    PubMed

    Xie, Wei; Schlücker, Sebastian

    2014-11-01

    Rationally designed multifunctional plasmonic nanostructures efficiently integrate two or more functionalities into a single entity, for example, with both plasmonic and catalytic activity. This review article is focused on their synthesis and use in surface-enhanced Raman scattering (SERS) as a molecular spectroscopic technique with high sensitivity, fingerprint specificity, and surface selectivity. After a short tutorial on the fundamentals of Raman scattering and SERS in particular, applications ranging from chemistry (heterogeneous catalysis) to biology and medicine (diagnostics/imaging, therapy) are summarized. PMID:25373417

  19. Rationally designed micropores within a metal-organic framework for selective sorption of gas molecules.

    PubMed

    Chen, Banglin; Ma, Shengqian; Zapata, Fatima; Fronczek, Frank R; Lobkovsky, Emil B; Zhou, Hong-Cai

    2007-02-19

    A microporous metal-organic framework, MOF, Cu(FMA)(4,4'-Bpe)0.5 (3a, FMA = fumarate; 4,4'-Bpe = 4,4'-Bpe = trans-bis(4-pyridyl)ethylene) was rationally designed from a primitive cubic net whose pores are tuned by double framework interpenetration. With pore cavities of about 3.6 A, which are interconnected by pore windows of 2.0 x 3.2 A, 3a shows highly selective sorption behaviors of gas molecules. PMID:17291116

  20. Crystals of Human Serum Albumin for Use in Genetic Engineering and Rational Drug Design

    NASA Technical Reports Server (NTRS)

    Carter, Daniel C. (Inventor)

    1994-01-01

    This invention pertains to crystals of serum albumin and processes for growing them. The purpose of the invention is to provide crystals of serum albumin which can be studied to determine binding sites for drugs. Form 2 crystals grow in the monoclinic space P2(sub 1), and possesses the following unit cell constraints: a = 58.9 +/- 7, b = 88.3 +/- 7, c = 60.7 +/- 7, Beta = 101.0 +/- 2 degrees. One advantage of the invention is that it will allow rational drug design

  1. A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies.

    PubMed

    van Beijnum, Judy R; Thijssen, Victor L; Läppchen, Tilman; Wong, Tse J; Verel, Iris; Engbersen, Maurits; Schulkens, Iris A; Rossin, Raffaella; Grüll, Holger; Griffioen, Arjan W; Nowak-Sliwinska, Patrycja

    2016-08-15

    Galectins are carbohydrate binding proteins that function in many key cellular processes. We have previously demonstrated that galectins are essential for tumor angiogenesis and their expression is associated with disease progression. Targeting galectins is therefore a potential anti-angiogenic and anti-cancer strategy. Here, we used a rational approach to generate antibodies against a specific member of this conserved protein family, i.e. galectin-1. We characterized two novel mouse monoclonal antibodies that specifically react with galectin-1 in human, mouse and chicken. We demonstrate that these antibodies are excellent tools to study galectin-1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin-1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin-1 in this process. PMID:27062254

  2. Identification of new snake venom metalloproteinase inhibitors using compound screening and rational Peptide design.

    PubMed

    Villalta-Romero, Fabián; Gortat, Anna; Herrera, Andrés E; Arguedas, Rebeca; Quesada, Javier; de Melo, Robson Lopes; Calvete, Juan J; Montero, Mavis; Murillo, Renato; Rucavado, Alexandra; Gutiérrez, José María; Pérez-Payá, Enrique

    2012-07-12

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  3. Rational design of nanofiber scaffolds for orthopedic tissue repair and regeneration

    PubMed Central

    Ma, Bing; Xie, Jingwei; Jiang, Jiang; Shuler, Franklin D; Bartlett, David E

    2013-01-01

    This article reviews recent significant advances in the design of nanofiber scaffolds for orthopedic tissue repair and regeneration. It begins with a brief introduction on the limitations of current approaches for orthopedic tissue repair and regeneration. It then illustrates that rationally designed scaffolds made up of electrospun nanofibers could be a promising solution to overcome the problems that current approaches encounter. The article also discusses the intriguing properties of electrospun nanofibers, including control of composition, structures, orders, alignments and mechanical properties, use as carriers for topical drug and/or gene sustained delivery, and serving as substrates for the regulation of cell behaviors, which could benefit musculoskeletal tissue repair and regeneration. It further highlights a few of the many recent applications of electrospun nanofiber scaffolds in repairing and regenerating various orthopedic tissues. Finally, the article concludes with perspectives on the challenges and future directions for better design, fabrication and utilization of nanofiber scaffolds for orthopedic tissue engineering. PMID:23987110

  4. Identification of New Snake Venom Metalloproteinase Inhibitors Using Compound Screening and Rational Peptide Design

    PubMed Central

    2012-01-01

    The majority of snakebite envenomations in Central America are caused by the viperid species Bothrops asper, whose venom contains a high proportion of zinc-dependent metalloproteinases that play a relevant role in the pathogenesis of hemorrhage characteristic of these envenomations. Broad metalloproteinase inhibitors, such as the peptidomimetic hydroxamate Batimastat, have been shown to inhibit snake venom metalloproteinases (SVMP). However, the difficulty in having open public access to Batimastat and similar molecules highlights the need to design new inhibitors of SVMPs that could be applied in the treatment of snakebite envenomations. We have chosen the SVMP BaP1 as a model to search for new inhibitors using different strategies, that is, screening of the Prestwick Chemical Library and rational peptide design. Results from these approaches provide clues on the structural requirements for efficient BaP1 inhibition and pave the way for the design of new inhibitors of SVMP. PMID:24900507

  5. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

    PubMed Central

    Attard, G; Sarker, D; Reid, A; Molife, R; Parker, C; de Bono, J S

    2006-01-01

    Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease. PMID:16983403

  6. Rational design of the column of a heavy multipurpose machining center

    NASA Astrophysics Data System (ADS)

    Atapin, V. V.; Kurlaev, N. V.

    2016-04-01

    The main purpose in the design of supporting constructions of heavy multipurpose machining center is the reduction of mass at the given precision and productivity of machining. Accomplish these ends the technology of rational design of supporting constructions is offered. This technology is based on the decomposition method and the finite elements method in the combination with optimization methods. The technology has four stages: 1) calculation of external forces and loads, 2) as a result the boundary conditions (force, kinematics) for individual supporting constructions are formed, 3) a problem about final optimal distribution of a material by the individual supporting constructions with the real cross-section is solved; 4) dynamic analysis. By the example of design of the column of a heavy multipurpose machining center the main stages of rational design of the individual supporting constructions are shown. At a design stage of the carrying system consisting of load-bearing structures with simplified geometry, optimum overall dimensions of the column are identified. For the admitted system of preferences, it is necessary to accept the fact that the carrying system with the column with the sizes of cross section of 1.8 m (along х axis) and 2.6 m (along y axis) is the best. The analysis of the work of the column under the torsion condition with the use of method of mechanics shows that the column with square cross sections = 2.46·2.46 m which rigidity on torsion is 26 % higher in comparison with a production version is the best. The results of calculation show that a production-release design of the column with longitudinal and transverse edges of rigidity is 24 % heavier than the column with the edges located on a diagonally at equal rigidity.

  7. The Use of Drug Discovery Tools in Rational Organometallic Catalyst Design

    SciTech Connect

    Sumpter, Bobby G; Drummond, Michael L

    2007-01-01

    A computational procedure is detailed where techniques common in the drug discovery process - 2D- and 3D-Quantitative Structure-Activity Relationships (QSAR) - are applied to rationalize the catalytic activity of a synthetically flexible, Ti-N=P ethylene polymerization catalyst system. Once models relating molecular properties to catalyst activity are built with the two QSAR approaches, two database mining approaches are used to select a small number of ligands from a larger database that are likely to produce catalysts with high activity when grafted onto the Ti-N=P framework.. The software employed throughout this work is freely available, easy to use, and was applied in a "black box" approach, to highlight areas where the drug discovery tools, designed to address organic molecules, have difficulty in addressing issues arising from the presence of a metal atom. In general, 3D-QSAR offers an efficient way to screen new potential ligands and separate those likely to lead to poor catalysts from those that are likely to contribute to highly active catalysts. The results for 2D-QSAR appear to be quantitatively unreliable, likely due to the presence of a metal atom; nonetheless, there is evidence that qualitative predictions from different models may be reliable. Pitfalls in the database mining techniques are identified, none of which are insurmountable. The lessons learned about the potential uses and drawbacks of the techniques described herein are readily applicable to other catalyst frameworks, thereby enabling a rational approach to catalyst improvement and design.

  8. Rational design and application of responsive α-helical peptide hydrogels

    NASA Astrophysics Data System (ADS)

    Banwell, Eleanor F.; Abelardo, Edgardo S.; Adams, Dave J.; Birchall, Martin A.; Corrigan, Adam; Donald, Athene M.; Kirkland, Mark; Serpell, Louise C.; Butler, Michael F.; Woolfson, Derek N.

    2009-07-01

    Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs, and as supports for cell growth and tissue engineering. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials. Here, we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks of fibrils melt on heating, whereas those formed through hydrophobic fibril-fibril interactions strengthen when warmed. The hSAFs are dual-peptide systems that gel only on mixing, which gives tight control over assembly. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture.

  9. Rational design of metal nitride redox materials for solar-driven ammonia synthesis.

    PubMed

    Michalsky, Ronald; Pfromm, Peter H; Steinfeld, Aldo

    2015-06-01

    Fixed nitrogen is an essential chemical building block for plant and animal protein, which makes ammonia (NH3) a central component of synthetic fertilizer for the global production of food and biofuels. A global project on artificial photosynthesis may foster the development of production technologies for renewable NH3 fertilizer, hydrogen carrier and combustion fuel. This article presents an alternative path for the production of NH3 from nitrogen, water and solar energy. The process is based on a thermochemical redox cycle driven by concentrated solar process heat at 700-1200°C that yields NH3 via the oxidation of a metal nitride with water. The metal nitride is recycled via solar-driven reduction of the oxidized redox material with nitrogen at atmospheric pressure. We employ electronic structure theory for the rational high-throughput design of novel metal nitride redox materials and to show how transition-metal doping controls the formation and consumption of nitrogen vacancies in metal nitrides. We confirm experimentally that iron doping of manganese nitride increases the concentration of nitrogen vacancies compared with no doping. The experiments are rationalized through the average energy of the dopant d-states, a descriptor for the theory-based design of advanced metal nitride redox materials to produce sustainable solar thermochemical ammonia. PMID:26052421

  10. Rational design and application of responsive α-helical peptide hydrogels

    PubMed Central

    Banwell, Eleanor F.; Abelardo, Edgardo S.; Adams, Dave J.; Birchall, Martin A.; Corrigan, Adam; Donald, Athene M.; Kirkland, Mark; Serpell, Louise C.; Butler, Michael F.; Woolfson, Derek N.

    2009-01-01

    Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs; and as supports for cell growth and tissue engineering1. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials2-4. Here we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks melt upon heating, whereas those formed via hydrophobic interactions strengthen when warmed. The hSAFs are dual-peptide systems that only gel on mixing, which gives tight control over assembly5. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture. PMID:19543314

  11. Rational design of metal nitride redox materials for solar-driven ammonia synthesis

    PubMed Central

    Michalsky, Ronald; Pfromm, Peter H.; Steinfeld, Aldo

    2015-01-01

    Fixed nitrogen is an essential chemical building block for plant and animal protein, which makes ammonia (NH3) a central component of synthetic fertilizer for the global production of food and biofuels. A global project on artificial photosynthesis may foster the development of production technologies for renewable NH3 fertilizer, hydrogen carrier and combustion fuel. This article presents an alternative path for the production of NH3 from nitrogen, water and solar energy. The process is based on a thermochemical redox cycle driven by concentrated solar process heat at 700–1200°C that yields NH3 via the oxidation of a metal nitride with water. The metal nitride is recycled via solar-driven reduction of the oxidized redox material with nitrogen at atmospheric pressure. We employ electronic structure theory for the rational high-throughput design of novel metal nitride redox materials and to show how transition-metal doping controls the formation and consumption of nitrogen vacancies in metal nitrides. We confirm experimentally that iron doping of manganese nitride increases the concentration of nitrogen vacancies compared with no doping. The experiments are rationalized through the average energy of the dopant d-states, a descriptor for the theory-based design of advanced metal nitride redox materials to produce sustainable solar thermochemical ammonia. PMID:26052421

  12. Rational Design of Chiral Nanostructures from Self-Assembly of a Ferrocene-Modified Dipeptide.

    PubMed

    Wang, Yuefei; Qi, Wei; Huang, Renliang; Yang, Xuejiao; Wang, Mengfan; Su, Rongxin; He, Zhimin

    2015-06-24

    We report a new paradigm for the rational design of chiral nanostructures that is based on the hierarchical self-assembly of a ferrocene (Fc)-modified dipeptide, ferrocene-L-Phe-L-Phe-OH (Fc-FF). Compared to other chiral self-assembling systems, Fc-FF is unique because of its smaller size, biocompatibility, multiple functions (a redox center), and environmental responsiveness. X-ray and spectroscopic analyses showed that the incorporation of counterions during the hierarchical self-assembly of Fc-FF changed the conformations of the secondary structures from flat β sheets into twisted β sheets. This approach enables chiral self-assembly and the formation of well-defined chiral nanostructures composed of helical twisted β sheets. We identified two elementary forms for the helical twist of the β sheets, which allowed us to create a rich variety of rigid chiral nanostructures over a wide range of scales. Furthermore, through subtle modulations in the counterions, temperature, and solvent, we are able to precisely control the helical pitch, diameter, and handedness of the self-assembled chiral nanostructures. This unprecedented level of control not only offers insights into how rationally designed chiral nanostructures can be formed from simple molecular building blocks but also is of significant practical value for the use in chiroptics, templates, chiral sensing, and separations. PMID:26018930

  13. Reviewing Ligand-Based Rational Drug Design: The Search for an ATP Synthase Inhibitor

    PubMed Central

    Lee, Chia-Hsien; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2011-01-01

    Following major advances in the field of medicinal chemistry, novel drugs can now be designed systematically, instead of relying on old trial and error approaches. Current drug design strategies can be classified as being either ligand- or structure-based depending on the design process. In this paper, by describing the search for an ATP synthase inhibitor, we review two frequently used approaches in ligand-based drug design: The pharmacophore model and the quantitative structure-activity relationship (QSAR) method. Moreover, since ATP synthase ligands are potentially useful drugs in cancer therapy, pharmacophore models were constructed to pave the way for novel inhibitor designs. PMID:21954360

  14. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies

    NASA Astrophysics Data System (ADS)

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-07-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm-2, which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles.

  15. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies

    PubMed Central

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-01-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm−2, which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles. PMID:26178865

  16. Rational Design of Polynuclear Organometallic Assemblies from a Simple Heteromultifunctional Ligand.

    PubMed

    Zhang, Long; Lin, Yue-Jian; Li, Zhen-Hua; Jin, Guo-Xin

    2015-10-28

    In modern coordination chemistry, supramolecular coordination complexes take advantage of ligand design to control the shapes and sizes of such architectures. Here we describe how to utilize starting building blocks and a multifunctional ligand to rationally design and synthesize different types of discrete assemblies. Using a hydroxamate ligand featuring two pair of chelating sites together with half-sandwich iridium and rhodium fragments, we were able to construct a series multinuclear organometallic macrocycles and cages through stepwise coordination-driven self-assembly. Experimental observations, supported by computational work, show that selective coordination modes were ascribed to the significant electronic density differences of the two chelating sites, (O,O') and (N,N'). The results underline the advantages of the discrimination between soft and hard binding sites, and suggest that hydroxamic acids can be used as a versatile class of facile multifunctional scaffold for the construction of novel two-dimensional and three-dimensional architectures. PMID:26440304

  17. Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection

    PubMed Central

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.

    2015-01-01

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. PMID:26125950

  18. Enhancing thermoelectric performance of Bi2Te3-based nanostructures through rational structure design.

    PubMed

    Hong, Min; Chen, Zhi-Gang; Yang, Lei; Zou, Jin

    2016-04-28

    Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures. PMID:27050933

  19. Rational design of crystalline supermicroporous covalent organic frameworks with triangular topologies.

    PubMed

    Dalapati, Sasanka; Addicoat, Matthew; Jin, Shangbin; Sakurai, Tsuneaki; Gao, Jia; Xu, Hong; Irle, Stephan; Seki, Shu; Jiang, Donglin

    2015-01-01

    Covalent organic frameworks (COFs) are an emerging class of highly ordered porous polymers with many potential applications. They are currently designed and synthesized through hexagonal and tetragonal topologies, limiting the access to and exploration of new structures and properties. Here, we report that a triangular topology can be developed for the rational design and synthesis of a new class of COFs. The triangular topology features small pore sizes down to 12 Å, which is among the smallest pores for COFs reported to date, and high π-column densities of up to 0.25 nm(-2), which exceeds those of supramolecular columnar π-arrays and other COF materials. These crystalline COFs facilitate π-cloud delocalization and are highly conductive, with a hole mobility that is among the highest reported for COFs and polygraphitic ensembles. PMID:26178865

  20. From G Protein-coupled Receptor Structure Resolution to Rational Drug Design*

    PubMed Central

    Jazayeri, Ali; Dias, Joao M.; Marshall, Fiona H.

    2015-01-01

    A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design. PMID:26100628

  1. Enhancing thermoelectric performance of Bi2Te3-based nanostructures through rational structure design

    NASA Astrophysics Data System (ADS)

    Hong, Min; Chen, Zhi-Gang; Yang, Lei; Zou, Jin

    2016-04-01

    Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures.Nanostructuring has been successfully employed to enhance the thermoelectric performance of Bi2Te3 due to its obtained low thermal conductivity. In order to further reduce the thermal conductivity, we designed a hierarchical nanostructure assembled with well-aligned Bi2Te3 nanoplates using Te nanotubes as templates by a facile microwave-assisted solvothermal synthesis. From the comparisons of their thermoelectric performance and theoretical calculations with simple Bi2Te3 nanostructures, we found that Te/Bi2Te3 hierarchical nanostructures exhibit a higher figure-of-merit due to the optimized reduced Fermi level and enhanced phonon scattering, as well as the suppressed bipolar conduction. This study provides an effective approach to enhance the thermoelectric performance of Bi2Te3-based nanostructures by rationally designing the nanostructures. Electronic supplementary information (ESI) available: XRD patterns, SEM and TEM images of as-synthesized Te nanotubes. See DOI: 10.1039/c6nr00719h

  2. Toward Rational Fragment-Based Lead Design without 3D Structures

    PubMed Central

    2012-01-01

    Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures. PMID:22889313

  3. Identification of SENP1 inhibitors through in silico screening and rational drug design.

    PubMed

    Zhao, Yaxue; Wang, Zhongli; Zhang, Jianchen; Zhou, Huchen

    2016-10-21

    The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 μM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed. PMID:27344494

  4. Rational design, synthesis and biological evaluation of modular fluorogenic substrates with high affinity and selectivity for PTP1B.

    PubMed

    Sanchini, Silvano; Perruccio, Francesca; Piizzi, Grazia

    2014-05-01

    Protein-tyrosine phosphatase 1B (PTP1B) is a key regulatory enzyme in several signal transduction pathways, and its upregulation has been associated with type-2 diabetes, obesity and cancer. Selective determination of the functional significance of PTP1B remains a major challenge because the activity of this crucial enzyme is currently evaluated through the use of fluorescent probes that lack selectivity and are limited to biochemical assays. Here we describe the rational design, synthesis and biological evaluation of new modular PTP1B fluorogenic substrates. The self-immolative 4-hydroxybenzyl alcohol has been used as a key component for the design of phosphotyrosine mimics linked to a latent chromophore, which is released through an enzyme-initiated domino reaction. Preliminary biological investigations showed that, by optimising the stereoelectronic properties and the binding interactions at the enzyme active site, it is possible to achieve substrates with high affinity and promising selectivity. Due to their modular nature, the synthesised fluorogenic probes represent versatile tools; customisation of the different subunits could widen the scope of these probes to a broader range of in vitro assays. Finally, these studies elucidate the critical role played by Asp181 in the PTP1B-catalysed dephosphorylation mechanism: disruption of the native conformation of this key amino acid residue on the WDP loop yields fluorogenic inhibitors, rather than substrates. For this reason, our studies also represent a step forward for the development of improved PTP1B noncovalent inhibitors. PMID:24719298

  5. Rational design of antibodies targeting specific epitopes within intrinsically disordered proteins

    PubMed Central

    Sormanni, Pietro; Aprile, Francesco A.; Vendruscolo, Michele

    2015-01-01

    Antibodies are powerful tools in life sciences research, as well as in diagnostic and therapeutic applications, because of their ability to bind given molecules with high affinity and specificity. Using current methods, however, it is laborious and sometimes difficult to generate antibodies to target specific epitopes within a protein, in particular if these epitopes are not effective antigens. Here we present a method to rationally design antibodies to enable them to bind virtually any chosen disordered epitope in a protein. The procedure consists in the sequence-based design of one or more complementary peptides targeting a selected disordered epitope and the subsequent grafting of such peptides on an antibody scaffold. We illustrate the method by designing six single-domain antibodies to bind different epitopes within three disease-related intrinsically disordered proteins and peptides (α-synuclein, Aβ42, and IAPP). Our results show that all these designed antibodies bind their targets with good affinity and specificity. As an example of an application, we show that one of these antibodies inhibits the aggregation of α-synuclein at substoichiometric concentrations and that binding occurs at the selected epitope. Taken together, these results indicate that the design strategy that we propose makes it possible to obtain antibodies targeting given epitopes in disordered proteins or protein regions. PMID:26216991

  6. Combining different design strategies for rational affinity maturation of the MICA-NKG2D interface

    PubMed Central

    Henager, Samuel H; Hale, Melissa A; Maurice, Nicholas J; Dunnington, Erin C; Swanson, Carter J; Peterson, Megan J; Ban, Joseph J; Culpepper, David J; Davies, Luke D; Sanders, Lisa K; McFarland, Benjamin J

    2012-01-01

    We redesigned residues on the surface of MICA, a protein that binds the homodimeric immunoreceptor NKG2D, to increase binding affinity with a series of rational, incremental changes. A fixed-backbone RosettaDesign protocol scored a set of initial mutations, which we tested by surface plasmon resonance for thermodynamics and kinetics of NKG2D binding, both singly and in combination. We combined the best four mutations at the surface with three affinity-enhancing mutations below the binding interface found with a previous design strategy. After curating design scores with three cross-validated tests, we found a linear relationship between free energy of binding and design score, and to a lesser extent, enthalpy and design score. Multiple mutants bound with substantial subadditivity, but in at least one case full additivity was observed when combining distant mutations. Altogether, combining the best mutations from the two strategies into a septuple mutant enhanced affinity by 50-fold, to 50 nM, demonstrating a simple, effective protocol for affinity enhancement. PMID:22761154

  7. Improving thermal and detergent stability of Bacillus stearothermophilus neopullulanase by rational enzyme design.

    PubMed

    Ece, Selin; Evran, Serap; Janda, Jan-Oliver; Merkl, Rainer; Sterner, Reinhard

    2015-06-01

    Neopullulanase, a glycosyl hydrolase from Bacillus stearothermophilus (bsNpl), is a potentially valuable enzyme for starch and detergent industries. However, as the protein is not active at elevated temperatures and high surfactant concentrations, we aimed to increase its stability by rational enzyme design. Nine potentially destabilizing cavities were identified in the crystal structure of the enzyme. Based on computational predictions, these cavities were filled by residues with bulkier side chains. The five Asp46Glu, Val239Leu, Val404Leu, Ser407Thr and Ala566Leu exchanges resulted in a drastic stabilization of bsNpl against inactivation by heat and detergents. The catalytic activity of the variants was identical to the wild-type enzyme. PMID:25680359

  8. Phenolic melanin precursors provide a rational approach to the design of antitumor agents for melanoma

    SciTech Connect

    Jimbow, K.; Miura, T.; Ito, S.; Ishikawa, K.

    1989-01-01

    A unique biological property of the melanocyte, melanin synthesis may permit a rational approach to design agents for better management of malignant melanoma. This in vivo and in vitro study examined the selective melanocytotoxicity and antimelanoma effects of phenolic compounds, cysteinylphenol (CP), cysteaminylphenol (CAP), and related compounds, and found (1) that both 4-S-CP and 4-S-CAP are melanin precursors, (2) that 4-S-CAP possesses a marked depigmenting potency with selective destruction of melanocytes in black follicles, and (3) a significant inhibition in the protein synthesis and tumor growth of B16 melanoma. Importantly, a whole body autoradiography indicated that these phenolic melanin precursors are selectively incorporated into melanoma tissues after i.p. administration.

  9. Rational design of metallic nanocavities for resonantly enhanced four-wave mixing

    PubMed Central

    Almeida, Euclides; Prior, Yehiam

    2015-01-01

    Optimizing the shape of nanostructures and nano-antennas for specific optical properties has evolved to be a very fruitful activity. With modern fabrication tools a large variety of possibilities is available for shaping both nanoparticles and nanocavities; in particular nanocavities in thin metal films have emerged as attractive candidates for new metamaterials and strong linear and nonlinear optical systems. Here we rationally design metallic nanocavities to boost their Four-Wave Mixing response by resonating the optical plasmonic resonances with the incoming and generated beams. The linear and nonlinear optical responses as well as the propagation of the electric fields inside the cavities are derived from the solution of Maxwell’s equations by using the 3D finite-differences time domain method. The observed conversion-efficiency of near-infrared to visible light equals or surpasses that of BBO of equivalent thickness. Implications to further optimization for efficient and broadband ultrathin nonlinear optical materials are discussed. PMID:25974175

  10. In silico rational design of ionic liquids for the exfoliation and dispersion of boron nitride nanosheets.

    PubMed

    García, Gregorio; Atilhan, Mert; Aparicio, Santiago

    2016-01-14

    A requirement for exploiting most of the unique properties of boron-nitride (BN) nanosheets is their isolation from the bulk material. A rational design of task-specific ionic liquids (ILs) through DFT simulations is reported in this work. The applied computational protocol allowed the screening of large IL families, which was carried out bearing in mind the achievement of strong π-π stacking between the anions and BN nanosheets as well as a negative charge transfer from the anion to the surface. The selected ionic liquids yielded strong interaction energies with BN nanosheets and high charge transfer values, while the main features of the ionic liquid are not affected in the presence of nanosheets. DFT simulations provided a detailed picture of the interaction mechanism and useful structure-property relationships in the search of a new ionic liquid for BN exfoliation. PMID:26658819

  11. From empiricism to rational design: a personal perspective of the evolution of vaccine development.

    PubMed

    De Gregorio, Ennio; Rappuoli, Rino

    2014-07-01

    Vaccination, which is the most effective medical intervention that has ever been introduced, originated from the observation that individuals who survived a plague or smallpox would not get the disease twice. To mimic the protective effects of natural infection, Jenner - and later Pasteur - inoculated individuals with attenuated or killed disease-causing agents. This empirical approach inspired a century of vaccine development and the effective prophylaxis of many infectious diseases. From the 1980s, several waves of new technologies have enabled the development of novel vaccines that would not have been possible using the empirical approach. The technological revolution in the field of vaccination is now continuing, and it is delivering novel and safer vaccines. In this Timeline article, we provide our views on the transition from empiricism to rational vaccine design. PMID:24925139

  12. Fibrin-based biomaterials: Modulation of macroscopic properties through rational design at the molecular level

    PubMed Central

    Brown, Ashley C.; Barker, Thomas H.

    2013-01-01

    Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach can now be somewhat easily modified through alterations of molecular interactions key to the protein’s polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials. PMID:24056097

  13. Evolving serodiagnostics by rationally designed peptide arrays: the Burkholderia paradigm in Cystic Fibrosis.

    PubMed

    Peri, Claudio; Gori, Alessandro; Gagni, Paola; Sola, Laura; Girelli, Daniela; Sottotetti, Samantha; Cariani, Lisa; Chiari, Marcella; Cretich, Marina; Colombo, Giorgio

    2016-01-01

    Efficient diagnosis of emerging and novel bacterial infections is fundamental to guide decisions on therapeutic treatments. Here, we engineered a novel rational strategy to design peptide microarray platforms, which combines structural and genomic analyses to predict the binding interfaces between diverse protein antigens and antibodies against Burkholderia cepacia complex infections present in the sera of Cystic Fibrosis (CF) patients. The predicted binding interfaces on the antigens are synthesized in the form of isolated peptides and chemically optimized for controlled orientation on the surface. Our platform displays multiple Burkholderia-related epitopes and is shown to diagnose infected individuals even in presence of superinfections caused by other prevalent CF pathogens, with limited cost and time requirements. Moreover, our data point out that the specific patterns determined by combined probe responses might provide a characterization of Burkholderia infections even at the subtype level (genomovars). The method is general and immediately applicable to other bacteria. PMID:27615705

  14. Enhancing the Acyltransferase Activity of Candida antarctica Lipase A by Rational Design.

    PubMed

    Müller, Janett; Sowa, Miriam A; Fredrich, Birte; Brundiek, Henrike; Bornscheuer, Uwe T

    2015-08-17

    A few lipases, such as Candida antarctica lipase A (CAL-A), are known to possess acyltransferase activity. This enables the enzyme to synthesize fatty acid esters from natural oils and alcohols even in the presence of bulk water. Unfortunately, fatty acids are still formed in these reactions as undesired side-products. To reduce the amount of fatty acids, several CAL-A variants were rationally designed based on its crystal structure. These variants were expressed in Escherichia coli and Pichia pastoris, purified, and their acyltransferase/hydrolase activities were investigated by various biocatalytic approaches. Among the investigated variants, mutant Asp122Leu showed a significant decrease in the hydrolytic activity, thus reducing the side-product yield during acylation. As desired, this variant retained wild-type process-relevant features like pH profile and thermostability. PMID:26058745

  15. Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering.

    PubMed

    Voigt, Franka; Wiedemann, Lisa; Zuliani, Cecilia; Querques, Irma; Sebe, Attila; Mátés, Lajos; Izsvák, Zsuzsanna; Ivics, Zoltán; Barabas, Orsolya

    2016-01-01

    Sleeping Beauty (SB) is a prominent Tc1/mariner superfamily DNA transposon that provides a popular genome engineering tool in a broad range of organisms. It is mobilized by a transposase enzyme that catalyses DNA cleavage and integration at short specific sequences at the transposon ends. To facilitate SB's applications, here we determine the crystal structure of the transposase catalytic domain and use it to model the SB transposase/transposon end/target DNA complex. Together with biochemical and cell-based transposition assays, our structure reveals mechanistic insights into SB transposition and rationalizes previous hyperactive transposase mutations. Moreover, our data enables us to design two additional hyperactive transposase variants. Our work provides a useful resource and proof-of-concept for structure-based engineering of tailored SB transposases. PMID:27025571

  16. Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering

    PubMed Central

    Voigt, Franka; Wiedemann, Lisa; Zuliani, Cecilia; Querques, Irma; Sebe, Attila; Mátés, Lajos; Izsvák, Zsuzsanna; Ivics, Zoltán; Barabas, Orsolya

    2016-01-01

    Sleeping Beauty (SB) is a prominent Tc1/mariner superfamily DNA transposon that provides a popular genome engineering tool in a broad range of organisms. It is mobilized by a transposase enzyme that catalyses DNA cleavage and integration at short specific sequences at the transposon ends. To facilitate SB's applications, here we determine the crystal structure of the transposase catalytic domain and use it to model the SB transposase/transposon end/target DNA complex. Together with biochemical and cell-based transposition assays, our structure reveals mechanistic insights into SB transposition and rationalizes previous hyperactive transposase mutations. Moreover, our data enables us to design two additional hyperactive transposase variants. Our work provides a useful resource and proof-of-concept for structure-based engineering of tailored SB transposases. PMID:27025571

  17. Rational design of DNA-actuated enzyme nanoreactors guided by single molecule analysis

    NASA Astrophysics Data System (ADS)

    Dhakal, Soma; Adendorff, Matthew R.; Liu, Minghui; Yan, Hao; Bathe, Mark; Walter, Nils G.

    2016-01-01

    The control of enzymatic reactions using nanoscale DNA devices offers a powerful application of DNA nanotechnology uniquely derived from actuation. However, previous characterization of enzymatic reaction rates using bulk biochemical assays reported suboptimal function of DNA devices such as tweezers. To gain mechanistic insight into this deficiency and to identify design rules to improve their function, here we exploit the synergy of single molecule imaging and computational modeling to characterize the three-dimensional structures and catalytic functions of DNA tweezer-actuated nanoreactors. Our analysis revealed two important deficiencies - incomplete closure upon actuation and conformational heterogeneity. Upon rational redesign of the Holliday junctions located at their hinge and arms, we found that the DNA tweezers could be more completely and uniformly closed. A novel single molecule enzyme assay was developed to demonstrate that our design improvements yield significant, independent enhancements in the fraction of active enzyme nanoreactors and their individual substrate turnover frequencies. The sequence-level design strategies explored here may aid more broadly in improving the performance of DNA-based nanodevices including biological and chemical sensors.The control of enzymatic reactions using nanoscale DNA devices offers a powerful application of DNA nanotechnology uniquely derived from actuation. However, previous characterization of enzymatic reaction rates using bulk biochemical assays reported suboptimal function of DNA devices such as tweezers. To gain mechanistic insight into this deficiency and to identify design rules to improve their function, here we exploit the synergy of single molecule imaging and computational modeling to characterize the three-dimensional structures and catalytic functions of DNA tweezer-actuated nanoreactors. Our analysis revealed two important deficiencies - incomplete closure upon actuation and conformational

  18. Rational design of modular circuits for gene transcription: A test of the bottom-up approach

    PubMed Central

    2010-01-01

    Background Most of synthetic circuits developed so far have been designed by an ad hoc approach, using a small number of components (i.e. LacI, TetR) and a trial and error strategy. We are at the point where an increasing number of modular, inter-changeable and well-characterized components is needed to expand the construction of synthetic devices and to allow a rational approach to the design. Results We used interchangeable modular biological parts to create a set of novel synthetic devices for controlling gene transcription, and we developed a mathematical model of the modular circuits. Model parameters were identified by experimental measurements from a subset of modular combinations. The model revealed an unexpected feature of the lactose repressor system, i.e. a residual binding affinity for the operator site by induced lactose repressor molecules. Once this residual affinity was taken into account, the model properly reproduced the experimental data from the training set. The parameters identified in the training set allowed the prediction of the behavior of networks not included in the identification procedure. Conclusions This study provides new quantitative evidences that the use of independent and well-characterized biological parts and mathematical modeling, what is called a bottom-up approach to the construction of gene networks, can allow the design of new and different devices re-using the same modular parts. PMID:21070658

  19. Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes

    PubMed Central

    Yun, Bo; Azad, Mohammad A. K.; Nowell, Cameron J.; Nation, Roger L.; Thompson, Philip E.; Roberts, Kade D.

    2015-01-01

    Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity. PMID:26392495

  20. Rational protein design: developing next-generation biological therapeutics and nanobiotechnological tools.

    PubMed

    Wilson, Corey J

    2015-01-01

    Proteins are the most functionally diverse macromolecules observed in nature, participating in a broad array of catalytic, biosensing, transport, scaffolding, and regulatory functions. Fittingly, proteins have become one of the most promising nanobiotechnological tools to date, and through the use of recombinant DNA and other laboratory methods we have produced a vast number of biological therapeutics derived from human genes. Our emerging ability to rationally design proteins (e.g., via computational methods) holds the promise of significantly expanding the number and diversity of protein therapies and has opened the gateway to realizing true and uncompromised personalized medicine. In the last decade computational protein design has been transformed from a set of fundamental strategies to stringently test our understanding of the protein structure-function relationship, to practical tools for developing useful biological processes, nano-devices, and novel therapeutics. As protein design strategies improve (i.e., in terms of accuracy and efficiency) clinicians will be able to leverage individual genetic data and biological metrics to develop and deliver personalized protein therapeutics with minimal delay. PMID:25348497

  1. Rational design of Nd(3+)-sensitized multifunctional nanoparticles with highly dominant red emission.

    PubMed

    Xu, Xia; Lei, Pengpeng; Dong, Lile; Liu, Xiuling; Su, Yue; Song, Shuyan; Feng, Jing; Zhang, Hongjie

    2016-05-28

    Controlling excitation and emission wavelengths on demand is very significant in bioimaging. Up-conversion nanoparticles (UCNPs) emit visible light upon near-infrared (NIR) light excitation and are well studied in bioimaging. Red emission is usually preferred to green due to its higher tissue penetration depth in bioimaging. Herein, dominant red emission has been achieved under 808 nm excitation based on the designed α-NaYbF4:Mn(2+)/Er(3+)@NaLuF4:Mn(2+)/Yb(3+)@NaNdF4:Yb(3+)@NaGdF4 (C@S1@S2@S3) nanostructure. The rationally designed interlayer shell NaLuF4:Mn(2+)/Yb(3+) could efficiently filter unwanted energy back-transfer from Er(3+) to Nd(3+) and the outmost shell NaGdF4 could prevent excitation energy from surface-related quenching. The lifetime of (4)F9/2→(4)I15/2 transition of Er(3+) could be as high as 0.7 ms. Moreover, C@S1@S2@S3 UCNPs also possess effective contrast efficiency for both X-ray computed tomography (CT) and magnetic resonance (MR) imaging. The designed multifunctional UCNPs could be used as a potential multimodal bioprobe in bioimaging applications. PMID:27111482

  2. Theory and simulation of DNA-coated colloids: a guide for rational design.

    PubMed

    Angioletti-Uberti, Stefano; Mognetti, Bortolo M; Frenkel, Daan

    2016-03-01

    By exploiting the exquisite selectivity of DNA hybridization, DNA-coated colloids (DNACCs) can be made to self-assemble in a wide variety of structures. The beauty of this system stems largely from its exceptional versatility and from the fact that a proper choice of the grafted DNA sequences yields fine control over the colloidal interactions. Theory and simulations have an important role to play in the optimal design of self assembling DNACCs. At present, the powerful model-based design tools are not widely used, because the theoretical literature is fragmented and the connection between different theories is often not evident. In this Perspective, we aim to discuss the similarities and differences between the different models that have been described in the literature, their underlying assumptions, their strengths and their weaknesses. Using the tools described in the present Review, it should be possible to move towards a more rational design of novel self-assembling structures of DNACCs and, more generally, of systems where ligand-receptor are used to control interactions. PMID:26862595

  3. Adapting Rational Unified Process (RUP) approach in designing a secure e-Tendering model

    NASA Astrophysics Data System (ADS)

    Mohd, Haslina; Robie, Muhammad Afdhal Muhammad; Baharom, Fauziah; Darus, Norida Muhd; Saip, Mohamed Ali; Yasin, Azman

    2016-08-01

    e-Tendering is an electronic processing of the tender document via internet and allow tenderer to publish, communicate, access, receive and submit all tender related information and documentation via internet. This study aims to design the e-Tendering system using Rational Unified Process approach. RUP provides a disciplined approach on how to assign tasks and responsibilities within the software development process. RUP has four phases that can assist researchers to adjust the requirements of various projects with different scope, problem and the size of projects. RUP is characterized as a use case driven, architecture centered, iterative and incremental process model. However the scope of this study only focusing on Inception and Elaboration phases as step to develop the model and perform only three of nine workflows (business modeling, requirements, analysis and design). RUP has a strong focus on documents and the activities in the inception and elaboration phases mainly concern the creation of diagrams and writing of textual descriptions. The UML notation and the software program, Star UML are used to support the design of e-Tendering. The e-Tendering design based on the RUP approach can contribute to e-Tendering developers and researchers in e-Tendering domain. In addition, this study also shows that the RUP is one of the best system development methodology that can be used as one of the research methodology in Software Engineering domain related to secured design of any observed application. This methodology has been tested in various studies in certain domains, such as in Simulation-based Decision Support, Security Requirement Engineering, Business Modeling and Secure System Requirement, and so forth. As a conclusion, these studies showed that the RUP one of a good research methodology that can be adapted in any Software Engineering (SE) research domain that required a few artifacts to be generated such as use case modeling, misuse case modeling, activity

  4. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

    PubMed

    Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

    2012-05-18

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence. PMID:22332923

  5. Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive

    PubMed Central

    Childs-Disney, Jessica L.; Hoskins, Jason; Rzuczek, Suzanne G.; Thornton, Charles A.; Disney, Matthew D.

    2012-01-01

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)exp, is present in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)exp folds into a hairpin with regularly repeating 5′CUG/3′GUC motifs and sequester muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1 including: (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)exp were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5′CUG/3′GUC motif in r(CUG)exp. Therefore, we designed multivalent ligands to bind multiple copies of this motif simultaneously in r(CUG)exp. Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence. PMID:22332923

  6. Rational design and validation of a vanilloid-sensitive TRPV2 ion channel.

    PubMed

    Yang, Fan; Vu, Simon; Yarov-Yarovoy, Vladimir; Zheng, Jie

    2016-06-28

    Vanilloids activation of TRPV1 represents an excellent model system of ligand-gated ion channels. Recent studies using cryo-electron microcopy (cryo-EM), computational analysis, and functional quantification revealed the location of capsaicin-binding site and critical residues mediating ligand-binding and channel activation. Based on these new findings, here we have successfully introduced high-affinity binding of capsaicin and resiniferatoxin to the vanilloid-insensitive TRPV2 channel, using a rationally designed minimal set of four point mutations (F467S-S498F-L505T-Q525E, termed TRPV2_Quad). We found that binding of resiniferatoxin activates TRPV2_Quad but the ligand-induced open state is relatively unstable, whereas binding of capsaicin to TRPV2_Quad antagonizes resiniferatoxin-induced activation likely through competition for the same binding sites. Using Rosetta-based molecular docking, we observed a common structural mechanism underlying vanilloids activation of TRPV1 and TRPV2_Quad, where the ligand serves as molecular "glue" that bridges the S4-S5 linker to the S1-S4 domain to open these channels. Our analysis revealed that capsaicin failed to activate TRPV2_Quad likely due to structural constraints preventing such bridge formation. These results not only validate our current working model for capsaicin activation of TRPV1 but also should help guide the design of drug candidate compounds for this important pain sensor. PMID:27298359

  7. Rational Design of Porous Conjugated Polymers and Roles of Residual Palladium for Photocatalytic Hydrogen Production.

    PubMed

    Li, Lianwei; Cai, Zhengxu; Wu, Qinghe; Lo, Wai-Yip; Zhang, Na; Chen, Lin X; Yu, Luping

    2016-06-22

    Developing highly efficient photocatalyts for water splitting is one of the grand challenges in solar energy conversion. Here, we report the rational design and synthesis of porous conjugated polymer (PCP) that photocatalytically generates hydrogen from water splitting. The design mimics natural photosynthetics systems with conjugated polymer component to harvest photons and the transition metal part to facilitate catalytic activities. A series of PCPs have been synthesized with different light harvesting chromophores and transition metal binding bipyridyl (bpy) sites. The photocatalytic activity of these bpy-containing PCPs can be greatly enhanced due to the improved light absorption, better wettability, local ordering structure, and the improved charge separation process. The PCP made of strong and fully conjugated donor chromophore DBD (M4) shows the highest hydrogen production rate at ∼33 μmol/h. The results indicate that copolymerization between a strong electron donor and weak electron acceptor into the same polymer chain is a useful strategy for developing efficient photocatalysts. This study also reveals that the residual palladium in the PCP networks plays a key role for the catalytic performance. The hydrogen generation activity of PCP photocatalyst can be further enhanced to 164 μmol/h with an apparent quantum yield of 1.8% at 350 nm by loading 2 wt % of extra platinum cocatalyst. PMID:27254306

  8. Rationally Designing Aptamer Sequences with Reduced Affinity for Controlled Sensor Performance

    PubMed Central

    Schoukroun-Barnes, Lauren R.; White, Ryan J.

    2015-01-01

    The relative ease of predicting the secondary structure of nucleic acid sequences lends itself to the design of sequences to perform desired functions. Here, we combine the utility of nucleic acid aptamers with predictable control over the secondary structure to rationally design sequences with controlled affinity towards a target analyte when employed as the recognition element in an electrochemical sensor. Specifically, we present a method to modify an existing high-gain aptamer sequence to create sequences that, when employed in an electrochemical, aptamer-based sensor, exhibit reduced affinity towards a small molecule analyte tobramycin. Sensors fabricated with the high-gain parent sequence saturate at concentrations much below the therapeutic window for tobramycin (7–18 µM). Accordingly, the rationale behind modifying this high-gain sequence to reduce binding affinity was to tune sensor performance for optimal sensitivity in the therapeutic window. Using secondary structure predictions and analysis of the NMR structure of an aminoglycoside RNA aptamer bound to tobramycin, we are able to successfully modify the aptamer sequence to tune the dissociation constants of electrochemical aptamer-based sensors between 0.17 and 3 µM. The guidelines we present represent a general strategy to lessening binding affinity of sensors employing aptamer-modified electrodes. PMID:25835184

  9. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    SciTech Connect

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.

  10. Rational design and adaptive management of combination therapies for Hepatitis C virus infection

    DOE PAGESBeta

    Ke, Ruian; Loverdo, Claude; Qi, Hangfei; Sun, Ren; Lloyd-Smith, James O.; Kouyos, Roger Dimitri

    2015-06-30

    Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensatemore » when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design.« less

  11. Rational Design of Biomolecular Templates for Synthesizing Multifunctional Noble Metal Nanoclusters toward Personalized Theranostic Applications.

    PubMed

    Yu, Yong; Mok, Beverly Y L; Loh, Xian Jun; Tan, Yen Nee

    2016-08-01

    Biomolecule-templated or biotemplated metal nanoclusters (NCs) are ultrasmall (<2 nm) metal (Au, Ag) particles stabilized by a certain type of biomolecular template (e.g., peptides, proteins, and DNA). Due to their unique physiochemical properties, biotemplated metal NCs have been widely used in sensing, imaging, delivery and therapy. The overwhelming applications in these individual areas imply the great promise of harnessing biotemplated metal NCs in more advanced biomedical aspects such as theranostics. Although applications of biotemplated metal NCs as theranostic agents are trending, the rational design of biomolecular templates suitable for the synthesis of multifunctional metal NCs for theranostics is comparatively underexplored. This progress report first identifies the essential attributes of biotemplated metal NCs for theranostics by reviewing the state-of-art applications in each of the four modalities of theranostics, namely sensing, imaging, delivery and therapy. To achieve high efficacy in these modalities, we elucidate the design principles underlying the use of biomolecules (proteins, peptides and nucleic acids) to control the NC size, emission color and surface chemistries for post-functionalization of therapeutic moieties. We then propose a unified strategy to engineer biomolecular templates that combine all these modalities to produce multifunctional biotemplated metal NCs that can serve as the next-generation personalized theranostic agents. PMID:27377035

  12. An approach to rational ligand-design based on a thermodynamic analysis.

    PubMed

    Ui, Mihoko; Tsumoto, Kouhei

    2010-11-01

    Thermodynamic analysis is an effective tool in screening of lead-compounds for development of potential drug candidates. In most cases, a ligand achieve high affinity and specificity to a target protein by means of both favorable enthalpy and entropy terms, which can be reflected in binding profiles of Isothermal Titration Calorimetry (ITC). A favorable enthalpy change suggests the contribution of noncovalent contacts such as hydrogen bonding and van der Waals interaction between a ligand and its target protein. In general, optimization of binding enthalpy is more difficult than that of entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its binding enthalpic gain. In this paper, we demonstrate the utility of thermodynamic approach to ligand screening using anti-ciguatoxin antibody 10C9 as a model of a target protein which possesses a large hydrophobic pocket. As a result of this screening, we have identified three compounds that could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. Comparison of their structure with the proper antigen ciguatoxin CTX3C revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. ITC measurement might be useful and powerful for a rational ligand screening and the optimization of the ligand; the enthalpic gain is an effective index for ligand-design studies. PMID:21171955

  13. Rational design and optimization of plasmonic nanoarrays for surface enhanced infrared spectroscopy

    PubMed Central

    Liberman, Vladimir; Adato, Ronen; Jeys, Thomas H.; Saar, Brian G.; Erramilli, Shyamsunder; Altug, Hatice

    2012-01-01

    We present an approach for rational design and optimization of plasmonic arrays for ultrasensitive surface enhanced infrared absorption (SEIRA) spectroscopy of specific protein analytes. Motivated by our previous work that demonstrated sub-attomole detection of surface-bound silk fibroin [Proc. Natl. Acad. Sci. U.S.A. 106, 19227 (2009)], we introduce here a general framework that allows for the numerical optimization of metamaterial sensor designs in order to maximize the absorbance signal. A critical feature of our method is the explicit compensation for the perturbative effects of the analyte's refractive index which alters the resonance frequency and line-shape of the metamaterial response, thereby leading to spectral distortion in SEIRA signatures. As an example, we leverage our method to optimize the geometry of periodic arrays of plasmonic nanoparticles on both Si and CaF2 substrates. The optimal geometries result in a three-order of magnitude absorbance enhancement compared to an unstructured Au layer, with the CaF2 substrate offering an additional factor of three enhancement in absorbance over a traditional Si substrate. The latter improvement arises from increase of near-field intensity over the Au nanobar surface for the lower index substrate. Finally, we perform sensitivity analysis for our optimized arrays to predict the effects of fabrication imperfections. We find that <20% deviation from the optimized absorbance response is readily achievable over large areas with modern nanofabrication techniques. PMID:22714181

  14. Rationally designed donor-acceptor scheme based molecules for applications in opto-electronic devices.

    PubMed

    Subash Sundar, T; Sen, R; Johari, P

    2016-04-01

    Several donor (D)-acceptor (A) based molecules are rationally designed by adopting three different schemes in which the conjugation length, strength of the donor and acceptor moieties, and planarity of the molecules are varied. These variations are made by introducing a π-conjugated linkage unit, terminating the ends of the moieties by different electron donating and accepting functional groups, and fusing the donor and acceptor moieties, respectively. Our DFT and TDDFT based calculations reveal that using the above-mentioned design schemes, the electronic and optical properties of the D-A based molecules can be largely tuned. While introduction of a linkage and fusing of moieties enhance the π-π interaction, addition of electron donating groups (-CH3, -OH, and -NH2) and electron accepting groups (-CF3, -CN, -NO2, and -NH3(+)) varies the strength of the donor and acceptor moieties. These factors lead to modulation of the HOMO and LUMO energy levels and facilitate the engineering of the HOMO-LUMO gap and the optical gap over a wide range of ∼0.7-3.7 eV. Moreover, on the basis of calculated ionization potential and reorganization energy, most of the investigated molecules are predicted to be air stable and to exhibit high electron mobility, with the possibility of the presence of ambipolar characteristics in a few of them. The results of our calculations not only demonstrate the examined molecules to be the potential materials for organic opto-electronic devices, but also establish an understanding of the composition-structure-property correlation, which will provide guidelines for designing and synthesizing new materials of choice. PMID:26972386

  15. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    SciTech Connect

    Chen, Chunlong; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald; De Yoreo, James J.

    2014-09-05

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic interactions (EI) and hydrophobic interactions (HI), with HI playing the dominant role. While either strong EI or HI inhibit growth and suppress (104) face expression, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate EI allow peptoids to weakly adsorb while moderate HI cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of (104) faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.

  16. Rational Design of Cathode Structure for High Rate Performance Lithium-Sulfur Batteries.

    PubMed

    Chen, Hongwei; Wang, Changhong; Dai, Yafei; Qiu, Shengqiang; Yang, Jinlong; Lu, Wei; Chen, Liwei

    2015-08-12

    Practical applications of Li-S batteries require not only high specific capacities and long cycle lifetimes but also high rate performance. We report a rationally designed Li-S cathode, which consists of a freestanding composite thin film assembled from S nanoparticles, reduced graphene oxide (rGO), and a multifunctional additive poly(anthraquinonyl sulfide) (PAQS). The S nanoparticles provide a high initial specific capacity, and the layered and porous rGO structure provides electron and ion transport paths and restricts polysulfide shuttling. PAQS is not only a highly efficient sulfide trapping agent but also an excellent Li(+) conductor, which benefits the battery reaction kinetics at a high rate. The resulting cathode exhibits an initial specific capacity of 1255 mAh g(-1) with a decay rate as low as 0.046% per cycles over 1200 cycles. Importantly, it displays a reversible capacity of 615 mAh g(-1) when discharged at a high rate of 8 C (13.744 A g(-1)). PMID:26148126

  17. Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

    PubMed Central

    Foller Larsen, Anders; Dumat, Blaise; Wranne, Moa S.; Lawson, Christopher P.; Preus, Søren; Bood, Mattias; Gradén, Henrik; Marcus Wilhelmsson, L.; Grøtli, Morten

    2015-01-01

    Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13-fold increased brightness (εΦF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment-insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs. PMID:26227585

  18. Rational design of novel cathode materials in solid oxide fuel cells using first-principles simulations

    NASA Astrophysics Data System (ADS)

    Choi, YongMan; Lin, M. C.; Liu, Meilin

    The search for clean and renewable sources of energy represents one of the most vital challenges facing us today. Solid oxide fuel cells (SOFCs) are among the most promising technologies for a clean and secure energy future due to their high energy efficiency and excellent fuel flexibility (e.g., direct utilization of hydrocarbons or renewable fuels). To make SOFCs economically competitive, however, development of new materials for low-temperature operation is essential. Here we report our results on a computational study to achieve rational design of SOFC cathodes with fast oxygen reduction kinetics and rapid ionic transport. Results suggest that surface catalytic properties are strongly correlated with the bulk transport properties in several material systems with the formula of La 0.5Sr 0.5BO 2.75 (where B = Cr, Mn, Fe, or Co). The predictions seem to agree qualitatively with available experimental results on these materials. This computational screening technique may guide us to search for high-efficiency cathode materials for a new generation of SOFCs.

  19. An Integrated Approach for the Rational Design of NanoVectors for Biomedical Imaging and Therapy

    PubMed Central

    Godin, Biana; Driessen, Wouter H.; Proneth, Bettina; Lee, Sei-Young; Srinivasan, Srimeenakshi; Rumbaut, Rolando; Arap, Wadih; Pasqualini, Renata; Ferrari, Mauro; Decuzzi, Paolo

    2013-01-01

    The use of nanoparticles for the early detection, cure and imaging of diseases has been proved already to have enormous potentials in different biomedical fields, as oncology and cardiology. A broad spectrum of nanoparticles are currently under development exhibiting differences in (i) size, ranging from few tens of nanometers to few microns; (ii) shape, from the classical spherical beads to discoidal, hemispherical, cylindrical and conical; (iii) surface functionalization, with a wide range of electrostatic charges and bio-molecule conjugations. Clearly, the library of nanoparticles generated by combining all possible sizes, shapes and surface physico-chemical properties is enormous. With such a complex scenario, an integrated approach is here proposed and described for the rational design of nanoparticle systems (nanovectors) for the intravascular delivery of therapeutic and imaging contrast agents. The proposed integrated approach combines multi-scale/multi-physics mathematical models with in-vitro assays and in-vivo intravital microscopy experiments and aims at identifying the optimal combination of size, shape and surface properties that maximize the nanovectors localization within the diseased microvasculature. PMID:20807601

  20. Staphylococcus aureus in Continuous Culture: A Tool for the Rational Design of Antibiotic Treatment Protocols

    PubMed Central

    Udekwu, Klas I.; Levin, Bruce R.

    2012-01-01

    In vitro measures of the pharmacodynamics of antibiotics that account for the factors anticipated for bacteria in infected patients are central to the rational design of antibiotic treatment protocols. We consider whether or not continuous culture devices are a way to obtain these measures. Staphylococcus aureus PS80 in high-density continuous cultures were exposed to oxacillin, ciprofloxacin, vancomycin, gentamicin, daptomycin and linezolid. Contrary to results from low density retentostats as well as to predictions of traditional PK/MIC ratios, daily dosing with up to 100× MIC did not clear these cultures. The densities of S. aureus in these cultures oscillated with constant amplitude and never fell below 105 CFU per ml. Save for daptomycin “treated” populations, the densities of bacteria in these cultures remained significantly below that of similar antibiotic-free cultures. Although these antibiotics varied in their pharmacodynamic properties there were only modest differences in their mean densities. Mathematical models and experiments suggest that the dominant factor preventing clearance was wall-adhering subpopulations reseeding the planktonic population which can be estimated and corrected for. Continuous cultures provide a way to evaluate the potential efficacy of antibiotic treatment regimes in vitro under conditions that are more clinically realistic and comprehensive than traditional in vitro PK/PD indices. PMID:22911681

  1. Development of bright fluorescent quadracyclic adenine analogues: TDDFT-calculation supported rational design

    NASA Astrophysics Data System (ADS)

    Foller Larsen, Anders; Dumat, Blaise; Wranne, Moa S.; Lawson, Christopher P.; Preus, Søren; Bood, Mattias; Gradén, Henrik; Marcus Wilhelmsson, L.; Grøtli, Morten

    2015-07-01

    Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13-fold increased brightness (ɛΦF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment-insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs.

  2. Engineering of genetic control tools in Synechocystis sp. PCC 6803 using rational design techniques.

    PubMed

    Albers, Stevan C; Gallegos, Victor A; Peebles, Christie A M

    2015-12-20

    Cyanobacteria show promise as photosynthetic microbial factories capable of harnessing sunlight and CO2 to produce valuable end products, but few genetic control tools have been characterized and utilized in these organisms. To develop a suite of control elements capable of gene control at a variety of expression strengths, a library of 10 promoter-constructs were developed and built via rational design techniques by adding individual nucleotides in a step-wise manner within the -10 and -35 cis-acting regions of the tac promoter. This suite produced a dynamic range of expression strength, exhibiting a 78 fold change between the lowest expressing promoter, Psca8- and the highest expressing promoter, Psca3-2 when tested within Synechocystis sp. PCC 6803. Additionally, this study details the construction of a chemically inducible construct for use in Synechocystis that is based on the tac repressor system most commonly used in Escherichia coli. This research demonstrates the construction of a highly expressed inducible promoter that is also capable of high levels of gene repression. Upon chemical induction with IPTG, this same mutant strain was capable of exhibiting an average 24X increase in GFP expression over that of the repressed state. PMID:26450561

  3. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    NASA Astrophysics Data System (ADS)

    Chen, Chun-Long; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald N.; Deyoreo, James J.

    2014-09-01

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic and hydrophobic interactions, with hydrophobic interactions playing the dominant role. While either strong electrostatic or hydrophobic interactions inhibit growth and reduces expression of the {104} faces, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate electrostatic interactions allow peptoids to weakly adsorb while moderate hydrophobic interactions cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of the {104} faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.

  4. Recovery of Red Fluorescent Protein Chromophore Maturation Deficiency through Rational Design

    PubMed Central

    Moore, Matthew M.; Oteng-Pabi, Samuel K.; Pandelieva, Antonia T.; Mayo, Stephen L.; Chica, Roberto A.

    2012-01-01

    Red fluorescent proteins (RFPs) derived from organisms in the class Anthozoa have found widespread application as imaging tools in biological research. For most imaging experiments, RFPs that mature quickly to the red chromophore and produce little or no green chromophore are most useful. In this study, we used rational design to convert a yellow fluorescent mPlum mutant to a red-emitting RFP without reverting any of the mutations causing the maturation deficiency and without altering the red chromophore’s covalent structure. We also created an optimized mPlum mutant (mPlum-E16P) that matures almost exclusively to the red chromophore. Analysis of the structure/function relationships in these proteins revealed two structural characteristics that are important for efficient red chromophore maturation in DsRed-derived RFPs. The first is the presence of a lysine residue at position 70 that is able to interact directly with the chromophore. The second is an absence of non-bonding interactions limiting the conformational flexibility at the peptide backbone that is oxidized during red chromophore formation. Satisfying or improving these structural features in other maturation-deficient RFPs may result in RFPs with faster and more complete maturation to the red chromophore. PMID:23285050

  5. Rational Design of Thermally Stable Novel Biocatalytic Nanomaterials: Enzyme Stability in Restricted Spatial Dimensions

    NASA Astrophysics Data System (ADS)

    Mudhivarthi, Vamsi K.

    Enzyme stability is of intense interest in bio-materials science as biocatalysts, and as sensing platforms. This is essentially because the unique properties of DNA, RNA, PAA can be coupled with the interesting and novel properties of proteins to produce systems with unprecedented control over their properties. In this article, the very first examples of enzyme/NA/inorganic hybrid nanomaterials and enzyme-Polyacrylic acid conjugates will be presented. The basic principles of design, synthesis and control of properties of these hybrid materials will be presented first, and this will be followed by a discussion of selected examples from our recent research findings. Data show that key properties of biological catalysts are improved by the inorganic framework especially when the catalyst is co-embedded with DNA. Several examples of such studies with various enzymes and proteins, including horseradish peroxidase (HRP), glucose oxidase (GO), cytochrome c (Cyt c), met-hemoglobin (Hb) and met-myoglobin (Mb) will be discussed. Additionally, key insights obtained by the standard methods of materials science including XRD, SEM and TEM as well as biochemical, calorimetric and spectroscopic methods will be discussed. Furthermore, improved structure and enhanced activities of the biocatalysts in specific cases will be demonstrated along with the potential stabilization mechanisms. Our hypothesis is that nucleic acids provide an excellent control over the enzyme-solid interactions as well as rational assembly of nanomaterials. These novel nanobiohybrid materials may aid in engineering more effective synthetic materials for gene-delivery, RNA-delivery and drug delivery applications.

  6. Rational design and controlled synthesis of Te/Bi2Te3 heterostructure nanostring composites

    NASA Astrophysics Data System (ADS)

    Zhang, Yuzhuo; Chen, Hong; Li, Zhiliang; Huang, Ting; Zheng, Shuqi

    2015-07-01

    Te/Bi2Te3 heterostructure nanostring composites composed of several Bi2Te3 nanoplates, which were perpendicularly strung together by Te nanorod, were rationally designed and synthesized via a facile solvothermal method on a large scale. The X-ray diffraction (XRD) characterization demonstrated that the Bi2Te3 nanoplates were rhombohedral phase and the Te nanorods were trigonal phase. The uniform nanostring morphologies were well characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM). Detailed heterostructures were proved via energy dispersive spectrometer (EDS) and high-resolution transmission electron microscope (HRTEM). The morphology transformation from Bi2Te3 nanoplates to Te/Bi2Te3 heterostructure nanostrings could be controlled by adjusting the ratio of bismuth oxide to tellurium oxide. NaOH, serving as catalytic reduction agent and morphology controlling agent, played an important role in the synthesis of Te/Bi2Te3 heterostructure nanostrings. The reaction mechanism was also proposed to explain the formation process of the composites and the specific function of reagents in this reaction system.

  7. 25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine

    PubMed Central

    Annabi, Nasim; Tamayol, Ali; Uquillas, Jorge Alfredo; Akbari, Mohsen; Bertassoni, Luiz E.; Cha, Chaenyung; Camci-Unal, Gulden; Dokmeci, Mehmet R.

    2014-01-01

    Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life. PMID:24741694

  8. Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.

    PubMed

    Beltramo, Massimiliano; Robert, Vincent; Galibert, Mathieu; Madinier, Jean-Baptiste; Marceau, Philippe; Dardente, Hugues; Decourt, Caroline; De Roux, Nicolas; Lomet, Didier; Delmas, Agnès F; Caraty, Alain; Aucagne, Vincent

    2015-04-23

    New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism. PMID:25811530

  9. Surface Termination of M1 Phase and Rational Design of Propane Ammoxidation Catalysts

    SciTech Connect

    Guliants, Vadim

    2015-02-16

    This final report describes major accomplishments in this research project which has demonstrated that the M1 phase is the only crystalline phase required for propane ammoxidation to acrylonitrile and that a surface monolayer terminating the ab planes of the M1 phase is responsible for their activity and selectivity in this reaction. Fundamental studies of the topmost surface chemistry and mechanism of propane ammoxidation over the Mo-V-(Te,Sb)-(Nb,Ta)-O M1 and M2 phases resulted in the development of quantitative understanding of the surface molecular structure – reactivity relationships for this unique catalytic system. These oxides possess unique catalytic properties among mixed metal oxides, because they selectively catalyze three alkane transformation reactions, namely propane ammoxidation to acrylonitrile, propane oxidation to acrylic acid and ethane oxidative dehydrogenation, all of considerable economic significance. Therefore, the larger goal of this research was to expand this catalysis to other alkanes of commercial interest, and more broadly, demonstrate successful approaches to rational design of improved catalysts that can be applied to other selective (amm)oxidation processes.

  10. Biomimetics: From Bioinformatics to Rational Design of Dendrimers as Gene Carriers

    PubMed Central

    Araya-Durán, Ingrid; Varas-Concha, Ignacio; Almonacid, Daniel Eduardo; González-Nilo, Fernando Danilo

    2015-01-01

    Biomimetics, or the use of principles of Nature for developing new materials, is a paradigm that could help Nanomedicine tremendously. One of the current challenges in Nanomedicine is the rational design of new efficient and safer gene carriers. Poly(amidoamine) (PAMAM) dendrimers are a well-known class of nanoparticles, extensively used as non-viral nucleic acid carriers, due to their positively charged end-groups. Yet, there are still several aspects that can be improved for their successful application in in vitro and in vivo systems, including their affinity for nucleic acids as well as lowering their cytotoxicity. In the search of new functional groups that could be used as new dendrimer-reactive groups, we followed a biomimetic approach to determine the amino acids with highest prevalence in protein-DNA interactions. Then we introduced them individually as terminal groups of dendrimers, generating a new class of nanoparticles. Molecular dynamics studies of two systems: PAMAM-Arg and PAMAM-Lys were also performed in order to describe the formation of complexes with DNA. Results confirmed that the introduction of amino acids as terminal groups in a dendrimer increases their affinity for DNA and the interactions in the complexes were characterized at atomic level. We end up by briefly discussing additional modifications that can be made to PAMAM dendrimers to turned them into promising new gene carriers. PMID:26382062

  11. Rational design of metal-organic electronic devices: A computational perspective

    NASA Astrophysics Data System (ADS)

    Chilukuri, Bhaskar

    engineers to choose the appropriate metal electrodes considering the chemical interactions at the interface. Additionally, the calculations performed on the interfaces provided valuable insight into binding energies, charge redistribution, change in the energy levels, dipole formation, etc., which are important parameters to consider while fabricating an electronic device. The research described in this dissertation highlights the application of unique computational modeling methods at different levels of theory to guide the experimental chemists and device engineers toward a rational design of transition metal based electronic devices with low cost and high performance.

  12. Rational risk-based decision support for drinking water well managers by optimized monitoring designs

    NASA Astrophysics Data System (ADS)

    Enzenhöfer, R.; Geiges, A.; Nowak, W.

    2011-12-01

    Advection-based well-head protection zones are commonly used to manage the contamination risk of drinking water wells. Considering the insufficient knowledge about hazards and transport properties within the catchment, current Water Safety Plans recommend that catchment managers and stakeholders know, control and monitor all possible hazards within the catchments and perform rational risk-based decisions. Our goal is to supply catchment managers with the required probabilistic risk information, and to generate tools that allow for optimal and rational allocation of resources between improved monitoring versus extended safety margins and risk mitigation measures. To support risk managers with the indispensable information, we address the epistemic uncertainty of advective-dispersive solute transport and well vulnerability (Enzenhoefer et al., 2011) within a stochastic simulation framework. Our framework can separate between uncertainty of contaminant location and actual dilution of peak concentrations by resolving heterogeneity with high-resolution Monte-Carlo simulation. To keep computational costs low, we solve the reverse temporal moment transport equation. Only in post-processing, we recover the time-dependent solute breakthrough curves and the deduced well vulnerability criteria from temporal moments by non-linear optimization. Our first step towards optimal risk management is optimal positioning of sampling locations and optimal choice of data types to reduce best the epistemic prediction uncertainty for well-head delineation, using the cross-bred Likelihood Uncertainty Estimator (CLUE, Leube et al., 2011) for optimal sampling design. Better monitoring leads to more reliable and realistic protection zones and thus helps catchment managers to better justify smaller, yet conservative safety margins. In order to allow an optimal choice in sampling strategies, we compare the trade-off in monitoring versus the delineation costs by accounting for ill

  13. Coupling molecular dynamics simulations with experiments for the rational design of indolicidin-analogous antimicrobial peptides.

    PubMed

    Tsai, Ching-Wei; Hsu, Ning-Yi; Wang, Chang-Hsu; Lu, Chia-Yu; Chang, Yung; Tsai, Hui-Hsu Gavin; Ruaan, Rouh-Chyu

    2009-09-25

    Antimicrobial peptides (AMPs) have attracted much interest in recent years because of their potential use as new-generation antibiotics. Indolicidin (IL) is a 13-residue cationic AMP that is effective against a broad spectrum of bacteria, fungi, and even viruses. Unfortunately, its high hemolytic activity retards its clinical applications. In this study, we adopted molecular dynamics (MD) simulations as an aid toward the rational design of IL analogues exhibiting high antimicrobial activity but low hemolysis. We employed long-timescale, multi-trajectory all-atom MD simulations to investigate the interactions of the peptide IL with model membranes. The lipid bilayer formed by the zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) was chosen as the model erythrocyte membrane; lipid bilayers formed from a mixture of POPC and the negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol were chosen to model bacterial membranes. MD simulations with a total simulation time of up to 4 micros revealed the mechanisms of the processes of IL adsorption onto and insertion into the membranes. The packing order of these lipid bilayers presumably correlated to the membrane stability upon IL adsorption and insertion. We used the degree of local membrane thinning and the reduction in the order parameter of the acyl chains of the lipids to characterize the membrane stability. The order of the mixed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol/POPC lipid bilayer reduced significantly upon the adsorption of IL. On the other hand, although the order of the pure-POPC lipid bilayer was perturbed slightly during the adsorption stage, the value was reduced more dramatically upon the insertion of IL into the membrane's hydrophobic region. The results imply that enhancing IL adsorption on the microbial membrane may amplify its antimicrobial activity, while the degree of hemolysis may be reduced through inhibition of IL insertion into the hydrophobic region

  14. Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein–Ligand Complexes

    PubMed Central

    2015-01-01

    Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein–ligand complexes. Such fluorine–backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin–MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogues by systematically changing the number of fluorine atoms, and we determined high-resolution crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin–MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine–backbone interactions in protein–ligand complexes, we developed a computational algorithm named FMAP, which calculates fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Analysis of the menin–MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine–backbone interactions may represent a particularly attractive approach to improve inhibitors of protein–protein interactions. PMID:26288158

  15. Rational design of the gram-scale synthesis of nearly monodisperse semiconductor nanocrystals

    PubMed Central

    2011-01-01

    We address two aspects of general interest for the chemical synthesis of colloidal semiconductor nanocrystals: (1) the rational design of the synthesis protocol aiming at the optimization of the reaction parameters in a minimum number of experiments; (2) the transfer of the procedure to the gram scale, while maintaining a low size distribution and maximizing the reaction yield. Concerning the first point, the design-of-experiment (DOE) method has been applied to the synthesis of colloidal CdSe nanocrystals. We demonstrate that 16 experiments, analyzed by means of a Taguchi L16 table, are sufficient to optimize the reaction parameters for controlling the mean size of the nanocrystals in a large range while keeping the size distribution narrow (5-10%). The DOE method strongly reduces the number of experiments necessary for the optimization as compared to trial-and-error approaches. Furthermore, the Taguchi table analysis reveals the degree of influence of each reaction parameter investigated (e.g., the nature and concentration of reagents, the solvent, the reaction temperature) and indicates the interactions between them. On the basis of these results, the synthesis has been scaled up by a factor of 20. Using a 2-L batch reactor combined with a high-throughput peristaltic pump, different-sized samples of CdSe nanocrystals with yields of 2-3 g per synthesis have been produced without sacrificing the narrow size distribution. In a similar setup, the gram-scale synthesis of CdSe/CdS/ZnS core/shell/shell nanocrystals exhibiting a fluorescence quantum yield of 81% and excellent resistance of the photoluminescence in presence of a fluorescent quencher (aromatic thiol) has been achieved. PACS: 81.20.Ka, 81.07.Bc, 78.67.Bf PMID:21791060

  16. Rational Concept for Designing Vapor-Liquid-Solid Growth of Single Crystalline Metal Oxide Nanowires.

    PubMed

    Klamchuen, Annop; Suzuki, Masaru; Nagashima, Kazuki; Yoshida, Hideto; Kanai, Masaki; Zhuge, Fuwei; He, Yong; Meng, Gang; Kai, Shoichi; Takeda, Seiji; Kawai, Tomoji; Yanagida, Takeshi

    2015-10-14

    Metal oxide nanowires hold great promise for various device applications due to their unique and robust physical properties in air and/or water and also due to their abundance on Earth. Vapor-liquid-solid (VLS) growth of metal oxide nanowires offers the high controllability of their diameters and spatial positions. In addition, VLS growth has applicability to axial and/or radial heterostructures, which are not attainable by other nanowire growth methods. However, material species available for the VLS growth of metal oxide nanowires are substantially limited even though the variety of material species, which has fascinating physical properties, is the most interesting feature of metal oxides. Here we demonstrate a rational design for the VLS growth of various metal oxide nanowires, based on the "material flux window". This material flux window describes the concept of VLS nanowire growth within a limited material flux range, where nucleation preferentially occurs only at a liquid-solid interface. Although the material flux was previously thought to affect primarily the growth rate, we experimentally and theoretically demonstrate that the material flux is the important experimental variable for the VLS growth of metal oxide nanowires. On the basis of the material flux window concept, we discover novel metal oxide nanowires, composed of MnO, CaO, Sm2O3, NiO, and Eu2O3, which were previously impossible to form via the VLS route. The newly grown NiO nanowires exhibited stable memristive properties superior to conventional polycrystalline devices due to the single crystallinity. Thus, this VLS design route offers a useful guideline for the discovery of single crystalline nanowires that are composed of functional metal oxide materials. PMID:26372675

  17. Intensive mutagenesis of the nisin hinge leads to the rational design of enhanced derivatives.

    PubMed

    Healy, Brian; Field, Des; O'Connor, Paula M; Hill, Colin; Cotter, Paul D; Ross, R Paul

    2013-01-01

    Nisin A is the most extensively studied lantibiotic and has been used as a preservative by the food industry since 1953. This 34 amino acid peptide contains three dehydrated amino acids and five thioether rings. These rings, resulting from one lanthionine and four methyllanthionine bridges, confer the peptide with its unique structure. Nisin A has two mechanisms of action, with the N-terminal domain of the peptide inhibiting cell wall synthesis through lipid II binding and the C-terminal domain responsible for pore-formation. The focus of this study is the three amino acid 'hinge' region (N 20, M 21 and K 22) which separates these two domains and allows for conformational flexibility. As all lantibiotics are gene encoded, novel variants can be generated through manipulation of the corresponding gene. A number of derivatives in which the hinge region was altered have previously been shown to possess enhanced antimicrobial activity. Here we take this approach further by employing simultaneous, indiscriminate site-saturation mutagenesis of all three hinge residues to create a novel bank of nisin derivative producers. Screening of this bank revealed that producers of peptides with hinge regions consisting of AAK, NAI and SLS displayed enhanced bioactivity against a variety of targets. These and other results suggested a preference for small, chiral amino acids within the hinge region, leading to the design and creation of producers of peptides with hinges consisting of AAA and SAA. These producers, and the corresponding peptides, exhibited enhanced bioactivity against Lactococcus lactis HP, Streptococcus agalactiae ATCC 13813, Mycobacterium smegmatis MC2155 and Staphylococcus aureus RF122 and thus represent the first example of nisin derivatives that possess enhanced activity as a consequence of rational design. PMID:24244524

  18. Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2

    PubMed Central

    Lee, Melissa M.; Pushechnikov, Alexei; Disney, Matthew D.

    2009-01-01

    Most ligands targeting RNA are identified through screening a therapeutic target for binding members of a ligand library. A potential alternative way to construct RNA binders is through rational design using information about the RNA motifs ligands prefer to bind. Herein, we describe such an approach to design modularly assembled ligands targeting the RNA that causes myotonic dystrophy type 2 (DM2), a currently untreatable disease. A previous study identified that 6′-N-5-hexynoate kanamycin A (1) prefers to bind 2×2 nucleotide, pyrimidine-rich RNA internal loops. Multiple copies of such loops were found in the RNA hairpin that causes DM2. The 1 ligand was then modularly displayed on a peptoid scaffold with varied number and spacing to target several internal loops simultaneously. Modularly assembled ligands were tested for binding to a series of RNAs and for inhibiting the formation of the toxic DM2 RNA-muscleblind protein (MBNL-1) interaction. The most potent ligand displays three 1 modules, each separated by four spacing submonomers, and inhibits the formation of the RNA-protein complex with an IC50 of 25 nM. This ligand is higher affinity and more specific for binding DM2 RNA than MBNL-1. It binds the DM2 RNA at least 20-times more tightly than related RNAs and 15-fold more tightly than MBNL-1. A related control peptoid displaying 6′-N-5-hexynoate neamine (2) is >100-fold less potent at inhibiting the RNA-protein interaction and binds to DM2 RNA >125-fold more weakly. Uptake studies into a mouse myoblast cell line also show that the most potent ligand is cell permeable. PMID:19348464

  19. Rational design and validation of a Tip60 histone acetyltransferase inhibitor

    NASA Astrophysics Data System (ADS)

    Gao, Chunxia; Bourke, Emer; Scobie, Martin; Famme, Melina Arcos; Koolmeister, Tobias; Helleday, Thomas; Eriksson, Leif A.; Lowndes, Noel F.; Brown, James A. L.

    2014-06-01

    Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

  20. Rational design and validation of a Tip60 histone acetyltransferase inhibitor

    PubMed Central

    Gao, Chunxia; Bourke, Emer; Scobie, Martin; Famme, Melina Arcos; Koolmeister, Tobias; Helleday, Thomas; Eriksson, Leif A.; Lowndes, Noel F.; Brown, James A. L.

    2014-01-01

    Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer. PMID:24947938

  1. Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery

    SciTech Connect

    Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

    2008-11-14

    A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.

  2. Toward the rational design of protein kinase casein kinase-2 inhibitors.

    PubMed

    Sarno, Stefania; Moro, Stefano; Meggio, Flavio; Zagotto, Giuseppe; Dal Ben, Diego; Ghisellini, Paola; Battistutta, Roberto; Zanotti, Giuseppe; Pinna, Lorenzo A

    2002-01-01

    Casein kinase-2 (CK2) probably is the most pleiotropic member of the protein kinase family, with more than 200 substrates known to date. Unlike the great majority of protein kinases, which are tightly regulated enzymes, CK2 is endowed with high constitutive activity, a feature that is suspected to underlie its oncogenic potential and possible implication in viral infections. This makes CK2 an attractive target for anti-neoplastic and antiviral drugs. Here, we present an overview of our present knowledge about CK2 inhibitors, with special reference to the information drawn from two recently solved crystal structures of CK2alpha in complex with emodin and with 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), this latter being the most specific CK2 inhibitor known to date. A comparison with a series of anthraquinone and xanthenone derivatives highlights the crucial relevance of the hydroxyl group at position 3 for inhibition by emodin, and discloses the possibility of increasing the inhibitory potency by placing an electron withdrawing group at position 5. We also present mutational data corroborating the relevance of two hydrophobic residues unique to CK2, Val66 and Ile174, for the interactions with emodin and TBB, but not with the flavonoid inhibitors quercetin and fisetin. In particular, the CK2alpha mutant V66A displays 27- and 11-fold higher IC(50) values with emodin and TBB, respectively, as compared with the wild-type, while the IC(50) value with quercetin is unchanged. The data presented pave the road toward the rational design of more potent and selective inhibitors of CK2 and the generation of CK2 mutants refractory to inhibition, useful to probe the implication of CK2 in specific cellular functions. PMID:12191608

  3. Rational design of on-chip refractive index sensors based on lattice plasmon resonances (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Lin, Linhan; Zheng, Yuebing

    2015-08-01

    Lattice plasmon resonances (LPRs), which originate from the plasmonic-photonic coupling in gold or silver nanoparticle arrays, possess ultra-narrow linewidth by suppressing the radiative damping and provide the possibility to develop the plasmonic sensors with high figure of merit (FOM). However, the plasmonic-photonic coupling is greatly suppressed when the nanoparticles are immobilized on substrates because the diffraction orders are cut off at the nanoparticle-substrate interfaces. Here, we develop the rational design of LPR structures for the high-performance, on-chip plasmonic sensors based on both orthogonal and parallel coupling. Our finite-difference time-domain simulations in the core/shell SiO2/Au nanocylinder arrays (NCAs) reveal that new modes of localized surface plasmon resonances (LSPRs) show up when the aspect ratio of the NCAs is increased. The height-induced LSPRs couple with the superstrate diffraction orders to generate the robust LPRs in asymmetric environment. The high wavelength sensitivity and narrow linewidth in these LPRs lead to the plasmonic sensors with high FOM and high signal-to-noise ratio (SNR). Wide working wavelengths from visible to near-infrared are also achieved by tuning the parameters of the NCAs. Moreover, the wide detection range of refractive index is obtained in the parallel LPR structure. The electromagnetic field distributions in the NCAs demonstrate the height-enabled tunability of the plasmonic "hot spots" at the sub-nanoparticles resolution and the coupling between these "hot spots" with the superstrate diffraction waves, which are responsible for the high performance LPRs-based on-chip refractive index sensors.

  4. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents.

    PubMed

    Santoshi, Seneha; Manchukonda, Naresh Kumar; Suri, Charu; Sharma, Manya; Sridhar, Balasubramanian; Joseph, Silja; Lopus, Manu; Kantevari, Srinivas; Baitharu, Iswar; Naik, Pradeep Kumar

    2015-03-01

    We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔG(bind, pred)) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔG(bind, expt) (calculated from the Kd value) are consistent with the predicted value of ΔG(bind, pred) calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further

  5. Rational Ligand Design for U(VI) and Pu(IV)

    SciTech Connect

    Szigethy, Geza

    2009-08-12

    Nuclear power is an attractive alternative to hydrocarbon-based energy production at a time when moving away from carbon-producing processes is widely accepted as a significant developmental need. Hence, the radioactive actinide power sources for this industry are necessarily becoming more widespread, which is accompanied by the increased risk of exposure to both biological and environmental systems. This, in turn, requires the development of technology designed to remove such radioactive threats efficiently and selectively from contaminated material, whether that be contained nuclear waste streams or the human body. Raymond and coworkers (University of California, Berkeley) have for decades investigated the interaction of biologically-inspired, hard Lewis-base ligands with high-valent, early-actinide cations. It has been established that such ligands bind strongly to the hard Lewis-acidic early actinides, and many poly-bidentate ligands have been developed and shown to be effective chelators of actinide contaminants in vivo. Work reported herein explores the effect of ligand geometry on the linear U(IV) dioxo dication (uranyl, UO2 2+). The goal is to utilize rational ligand design to develop ligands that exhibit shape selectivity towards linear dioxo cations and provides thermodynamically favorable binding interactions. The uranyl complexes with a series of tetradentate 3-hydroxy-pyridin-2-one (3,2-HOPO) ligands were studied in both the crystalline state as well as in solution. Despite significant geometric differences, the uranyl affinities of these ligands vary only slightly but are better than DTPA, the only FDA-approved chelation therapy for actinide contamination. The terepthalamide (TAM) moiety was combined into tris-beidentate ligands with 1,2- and 3,2-HOPO moieties were combined into hexadentate ligands whose structural preferences and solution thermodynamics were measured with the uranyl cation. In addition to achieving coordinative

  6. Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.

    PubMed

    Luz, John Gately; Antonysamy, Stephen; Kuklish, Steven L; Condon, Bradley; Lee, Matthew R; Allison, Dagart; Yu, Xiao-Peng; Chandrasekhar, Srinivasan; Backer, Ryan; Zhang, Aiping; Russell, Marijane; Chang, Shawn S; Harvey, Anita; Sloan, Ashley V; Fisher, Matthew J

    2015-06-11

    Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies. PMID:25961169

  7. New Study Designs | Division of Cancer Prevention

    Cancer.gov

    The Division of Cancer Prevention is expanding clinical research beyond standard trial designs to find interventions that may play a role in more than one prevalent disease. | The Division of Cancer Prevention is expanding clinical research beyond standard trial designs to find interventions that may play a role in more than one prevalent disease.

  8. Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab.

    PubMed

    Courtois, Fabienne; Agrawal, Neeraj J; Lauer, Timothy M; Trout, Bernhardt L

    2016-01-01

    The aggregation of biotherapeutics is a major hindrance to the development of successful drug candidates; however, the propensity to aggregate is often identified too late in the development phase to permit modification to the protein's sequence. Incorporating rational design for the stability of proteins in early discovery has numerous benefits. We engineered out aggregation-prone regions on the Fab domain of a therapeutic monoclonal antibody, bevacizumab, to rationally design a biobetter drug candidate. With the purpose of stabilizing bevacizumab with respect to aggregation, 2 strategies were undertaken: single point mutations of aggregation-prone residues and engineering a glycosylation site near aggregation-prone residues to mask these residues with a carbohydrate moiety. Both of these approaches lead to comparable decreases in aggregation, with an up to 4-fold reduction in monomer loss. These single mutations and the new glycosylation pattern of the Fab domain do not modify binding to the target. Biobetters with increased stability against aggregation can therefore be generated in a rational manner, by either removing or masking the aggregation-prone region or crowding out protein-protein interactions. PMID:26514585

  9. Improvements in Rational Design Strategies of Inulin Derivative Polycation for siRNA Delivery.

    PubMed

    Sardo, Carla; Craparo, Emanuela Fabiola; Porsio, Barbara; Giammona, Gaetano; Cavallaro, Gennara

    2016-07-11

    The advances of short interfering RNA (siRNA)-mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA/siRNA "Inulin COmplex Nanoaggregates" (ICONs). The experimental results showed that INU-IMI-DETA exhibited strong cationic characteristics and high solubility in the pH range 3-5 and self-aggregation triggered by pH increase and physiological salt concentration. INU-IMI-DETA showed as well a high buffering capacity in the endosomal pH range of 7.4-5.1. In the concentration range between 25 and 1000 μg/mL INU-IMI-DETA had no cytotoxic effect on breast cancer cells (MCF-7) and no lytic effect on human red blood cells. ICONs were prepared by two-step procedure involving complexation and precipitation into DPBS buffer (pH 7.4) to produce siRNA-loaded nanoaggregates with minimized surface charge and suitable size for parenteral administration. Bafilomycin A1 inhibited transfection on MCF-7 cells, indicating that the protonation of the imidazole groups in the endolysosome pathway favors the escape of the system from endolysosomal compartment, increasing the amount of siRNA that can reach the cytoplasm. PMID:27238382

  10. Rationally Designed Interfacial Peptides Are Efficient In Vitro Inhibitors of HIV-1 Capsid Assembly with Antiviral Activity

    PubMed Central

    Bocanegra, Rebeca; Nevot, María; Doménech, Rosa; López, Inmaculada; Abián, Olga; Rodríguez-Huete, Alicia; Cavasotto, Claudio N.; Velázquez-Campoy, Adrián; Gómez, Javier; Martínez, Miguel Ángel; Neira, José Luis; Mateu, Mauricio G.

    2011-01-01

    Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly

  11. Molecular Epigenetics in the Management of Ovarian Cancer: Are We Investigating a Rational Clinical Promise?

    PubMed Central

    Nguyen, Ha T.; Tian, Geng; Murph, Mandi M.

    2014-01-01

    Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. Although liquid tumors are benefiting from epigenetically related therapies, solid tumors like ovarian cancer are not (yet?). Herein, we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Pre-clinical and clinical research on the role of epigenetic modifications is also summarized. Unfortunately, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management, which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have pre-clinical utility in pharmacology and clinical applications for prognosis and diagnosis. Finally, drugs currently in clinical trials (i.e., histone deacetylase inhibitors) are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; but we hope so in the future. PMID:24782983

  12. Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer.

    PubMed

    Bransi, Ali; Salgado, Oscar Camilo; Beffinger, Michal; Milo, Karim; Silina, Karina; Yagita, Hideo; Becher, Burkhard; Knuth, Alexander; van den Broek, Maries

    2015-11-01

    In the context of cancer, naïve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 + IL2/anti-IL2 complexes + IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8(+) T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer. PMID:26141620

  13. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics

    PubMed Central

    Philipp, Jenny; Künze, Georg; Wodtke, Robert; Löser, Reik; Fahmy, Karim; Pisabarro, M. Teresa

    2016-01-01

    Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands. PMID:27123592

  14. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics.

    PubMed

    Ruiz-Gómez, Gloria; Hawkins, John C; Philipp, Jenny; Künze, Georg; Wodtke, Robert; Löser, Reik; Fahmy, Karim; Pisabarro, M Teresa

    2016-01-01

    Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands. PMID:27123592

  15. Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer.

    PubMed

    Ross, A E; D'Amico, A V; Freedland, S J

    2016-03-01

    An increased molecular understanding of localized prostate cancer and the improved ability for molecular testing of pathologic tissue has led to the development of multiple clinical assays. Here we review the relevant molecular biology of localized prostate cancer, currently available tissue-based tests and describe which is best supported for use in various clinical scenarios. Literature regarding testing of human prostate cancer tissue with Ki-67, PTEN (by immunohistochemistry (IHC) or fluroescence in situ hybridization (FISH)), ProMark, Prolaris, OncotypeDX Prostate and Decipher was reviewed to allow for generation of expert opinions. At diagnosis, evaluation of PTEN status, use of ProMark or OncotypeDX Prostate in men with Gleason 6 or 3+4=7 disease may help guide the use of active surveillance. For men with Gleason 7 or above disease considering watchful waiting, Ki-67 and Prolaris add independent prognostic information. For those men who have undergone prostatectomy and have adverse pathology, Decipher testing may aid in the decision to undergo adjuvant radiation. Newly available molecular tests bring opportunities to improve decision making for men with localized prostate cancer. A review of the currently available data suggests clinical scenarios for which each of these tests may have the greatest utility. PMID:26123120

  16. Elementary Mode Analysis for the Rational Design of Efficient Succinate Conversion from Glycerol by Escherichia coli

    PubMed Central

    Chen, Zhen; Liu, Hongjuan; Zhang, Jianan; Liu, Dehua

    2010-01-01

    By integrating the restriction of oxygen and redox sensing/regulatory system, elementary mode analysis was used to predict the metabolic potential of glycerol for succinate production by E. coli under either anaerobic or aerobic conditions. It was found that although the theoretical maximum succinate yields under both anaerobic and aerobic conditions are 1.0 mol/mol glycerol, the aerobic condition was considered to be more favorable for succinate production. Although increase of the oxygen concentration would reduce the succinate yield, the calculation suggests that controlling the molar fraction of oxygen to be under 0.65 mol/mol would be beneficial for increasing the succinate productivity. Based on the elementary mode analysis, the rational genetic modification strategies for efficient succinate production under aerobic and anaerobic conditions were obtained, respectively. Overexpressing the phosphoenolpyruvate carboxylase or heterogonous pyruvate carboxylase is considered to be the most efficient strategy to increase the succinate yield. PMID:20886007

  17. A Rationally Designed Connector for Assembly of Protein-Functionalized DNA Nanostructures.

    PubMed

    Koßmann, Katja J; Ziegler, Cornelia; Angelin, Alessandro; Meyer, Rebecca; Skoupi, Marc; Rabe, Kersten S; Niemeyer, Christof M

    2016-06-16

    We report on the rational engineering of the binding interface of the self-ligating HaloTag protein to generate an optimized linker for DNA nanostructures. Five amino acids positioned around the active-site entry channel for the chlorohexyl ligand (CH) of the HaloTag protein were exchanged for positively charged lysine amino acids to produce the HOB (halo-based oligonucleotide binder) protein. HOB was genetically fused with the enzyme cytochrome P450 BM3, as well as with BMR, the separated reductase domain of BM3. The resulting HOB-fusion proteins revealed significantly improved rates in ligation with CH-modified oligonucleotides and DNA origami nanostructures. These results suggest that the efficient self-assembly of protein-decorated DNA structures can be greatly improved by fine-tuning of the electrostatic interactions between proteins and the negatively charged nucleic acid nanostructures. PMID:26972311

  18. [Hygienic characteristics of daily ration, designed for military servicemen doing call-up military service].

    PubMed

    Smagulov, N K; Mukhametzhanov, A M

    2016-01-01

    The article gives the hygienic characteristics of the daily diet of soldiers doing call-up military service. The object of study--military servicemen aged 18-22 years doing call-up military service. The material of the study data was obtained from a continuous cross-sectional study of dietary intake among military personnel. Investigation pointed out that consumption of nutrients and energy value of the surveyed military personnel was broadly in accordance with recommended physiological requirements for nutrients and energy for this age group. However; despite the adequacy of energy supply, showed signs of imbalance on the nutrients of rations provided in the military establishment. Structure of consumption of products is not in full compliance with the existing recommendations of the Kazakh academy of Nutrition. PMID:27120954

  19. Toward rational design of organic dye sensitized solar cells (DSSCs): an application to the TA-St-CA dye.

    PubMed

    Mohammadi, Narges; Mahon, Peter J; Wang, Feng

    2013-03-01

    A computer aided rational design has been performed on TA-St-CA dye sensitizer in order to improve the desirable properties for new organic dye sensitized solar cell (DSSC). A number of electron-donating (ED) and electron-withdrawing (EW) units based on Dewar's rules are substituted into the π-conjugated oligo-phenylenevinylene bridge of the reference TA-St-CA dye. The effects of these alternations on the molecular structures and the electron absorption spectra are calculated using time-dependant density functional theory (TDDFT). It is found that chemical modifications using electron donating (ED) substitutions exhibit advantages over the electron withdrawing (EW) substitutes to reduce the HOMO-LUMO energy gap as well as the electron distribution of the frontier orbitals of the new dyes. Dewar's rule is a useful guideline for rational design of new dye sensitizers with desired HOMO-LUMO gap. The impact on the optical spectra of new dyes are, however, less significant. PMID:23353583

  20. Hierarchical N-Doped Carbon as CO2 Adsorbent with High CO2 Selectivity from Rationally Designed Polypyrrole Precursor.

    PubMed

    To, John W F; He, Jiajun; Mei, Jianguo; Haghpanah, Reza; Chen, Zheng; Kurosawa, Tadanori; Chen, Shucheng; Bae, Won-Gyu; Pan, Lijia; Tok, Jeffrey B-H; Wilcox, Jennifer; Bao, Zhenan

    2016-01-27

    Carbon capture and sequestration from point sources is an important component in the CO2 emission mitigation portfolio. In particular, sorbents with both high capacity and selectivity are required for reducing the cost of carbon capture. Although physisorbents have the advantage of low energy consumption for regeneration, it remains a challenge to obtain both high capacity and sufficient CO2/N2 selectivity at the same time. Here, we report the controlled synthesis of a novel N-doped hierarchical carbon that exhibits record-high Henry's law CO2/N2 selectivity among physisorptive carbons while having a high CO2 adsorption capacity. Specifically, our synthesis involves the rational design of a modified pyrrole molecule that can co-assemble with the soft Pluronic template via hydrogen bonding and electrostatic interactions to give rise to mesopores followed by carbonization. The low-temperature carbonization and activation processes allow for the development of ultrasmall pores (d < 0.5 nm) and preservation of nitrogen moieties, essential for enhanced CO2 affinity. Furthermore, our described work provides a strategy to initiate developments of rationally designed porous conjugated polymer structures and carbon-based materials for various potential applications. PMID:26717034

  1. Protein engineering of Bacillus acidopullulyticus pullulanase for enhanced thermostability using in silico data driven rational design methods.

    PubMed

    Chen, Ana; Li, Yamei; Nie, Jianqi; McNeil, Brian; Jeffrey, Laura; Yang, Yankun; Bai, Zhonghu

    2015-10-01

    Thermostability has been considered as a requirement in the starch processing industry to maintain high catalytic activity of pullulanase under high temperatures. Four data driven rational design methods (B-FITTER, proline theory, PoPMuSiC-2.1, and sequence consensus approach) were adopted to identify the key residue potential links with thermostability, and 39 residues of Bacillus acidopullulyticus pullulanase were chosen as mutagenesis targets. Single mutagenesis followed by combined mutagenesis resulted in the best mutant E518I-S662R-Q706P, which exhibited an 11-fold half-life improvement at 60 °C and a 9.5 °C increase in Tm. The optimum temperature of the mutant increased from 60 to 65 °C. Fluorescence spectroscopy results demonstrated that the tertiary structure of the mutant enzyme was more compact than that of the wild-type (WT) enzyme. Structural change analysis revealed that the increase in thermostability was most probably caused by a combination of lower stability free-energy and higher hydrophobicity of E518I, more hydrogen bonds of S662R, and higher rigidity of Q706P compared with the WT. The findings demonstrated the effectiveness of combined data-driven rational design approaches in engineering an industrial enzyme to improve thermostability. PMID:26215347

  2. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer

    PubMed Central

    Thurn, K Ted; Thomas, Scott; Moore, Amy; Munster, Pamela N

    2011-01-01

    Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach. PMID:21345145

  3. Rational design of a binary metal alloy for chemical vapour deposition growth of uniform single-layer graphene.

    PubMed

    Dai, Boya; Fu, Lei; Zou, Zhiyu; Wang, Min; Xu, Haitao; Wang, Sheng; Liu, Zhongfan

    2011-01-01

    Controlled growth of high-quality graphene is still the bottleneck of practical applications. The widely used chemical vapour deposition process generally suffers from an uncontrollable carbon precipitation effect that leads to inhomogeneous growth and strong correlation to the growth conditions. Here we report the rational design of a binary metal alloy that effectively suppresses the carbon precipitation process and activates a self-limited growth mechanism for homogeneous monolayer graphene. As demonstrated by an Ni-Mo alloy, the designed binary alloy contains an active catalyst component for carbon source decomposition and graphene growth and a black hole counterpart for trapping the dissolved carbons and forming stable metal carbides. This type of process engineering has been used to grow strictly single-layer graphene with 100% surface coverage and excellent tolerance to variations in growth conditions. With simplicity, scalability and a very large growth window, the presented approach may facilitate graphene research and industrial applications. PMID:22045001

  4. Improved detection of botulinum type E by rational design of a new peptide substrate for endopeptidase-mass spectrometry assay.

    PubMed

    Rosen, Osnat; Feldberg, Liron; Gura, Sigalit; Zichel, Ran

    2014-07-01

    Botulinum neurotoxins (BoNTs) are the most toxic substances known to humans. Endopeptidase-mass spectrometry (Endopep-MS) is used as a specific and rapid in vitro assay to detect BoNTs. In this assay, immunocaptured toxin cleaves a serotype-specific peptide substrate, and the cleavage products are then detected by MS. To further improve the sensitivity of the assay, we report here the rational design of a new substrate peptide for the detection of botulinum neurotoxin type E (BoNT/E). Our strategy was based on previously reported structural interactions integrated with analysis method efficiency considerations. Integration of the newly designed substrate has led to a more than one order of magnitude increased sensitivity of the assay. PMID:24721293

  5. Rational Design of Methodology-Independent Metal Parameters Using a Nonbonded Dummy Model.

    PubMed

    Jiang, Yang; Zhang, Haiyang; Tan, Tianwei

    2016-07-12

    A nonbonded dummy model for metal ions is highly imperative for the computation of complex biological systems with for instance multiple metal centers. Here we present nonbonded dummy parameters of 11 divalent metallic cations, namely, Mg(2+), V(2+), Cr(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Cd(2+), Sn(2+), and Hg(2+), that are optimized to be compatible with three widely used water models (TIP3P, SPC/E, and TIP4P-EW). The three sets of metal parameters reproduce simultaneously the solvation free energies (ΔGsol), the ion-oxygen distance in the first solvation shell (IOD), and coordination numbers (CN) in explicit water with a relative error less than 1%. The main sources of errors to ΔGsol that arise from the boundary conditions and treatment of electrostatic interactions are corrected rationally, which ensures the independence of the proposed parameters on the methodology used in the calculation. This work will be of great value for the computational study of metal-containing biological systems. PMID:27182744

  6. Designing of skull defect implants using C1 rational cubic Bezier and offset curves

    NASA Astrophysics Data System (ADS)

    Mohamed, Najihah; Majid, Ahmad Abd; Piah, Abd Rahni Mt; Rajion, Zainul Ahmad

    2015-05-01

    Some of the reasons to construct skull implant are due to head trauma after an accident or an injury or an infection or because of tumor invasion or when autogenous bone is not suitable for replacement after a decompressive craniectomy (DC). The main objective of our study is to develop a simple method to redesign missing parts of the skull. The procedure begins with segmentation, data approximation, and estimation process of the outer wall by a C1 continuous curve. Its offset curve is used to generate the inner wall. A metaheuristic algorithm, called harmony search (HS) is a derivative-free real parameter optimization algorithm inspired from the musical improvisation process of searching for a perfect state of harmony. In this study, data approximation by a rational cubic Bézier function uses HS to optimize position of middle points and value of the weights. All the phases contribute significantly in making our proposed technique automated. Graphical examples of several postoperative skulls are displayed to show the effectiveness of our proposed method.

  7. Physics of icing and rational design of surfaces with extraordinary icephobicity.

    PubMed

    Schutzius, Thomas M; Jung, Stefan; Maitra, Tanmoy; Eberle, Patric; Antonini, Carlo; Stamatopoulos, Christos; Poulikakos, Dimos

    2015-05-01

    Icing of surfaces is commonplace in nature and technology, affecting everyday life and sometimes causing catastrophic events. Understanding (and counteracting) surface icing brings with it significant scientific challenges that requires interdisciplinary knowledge from diverse scientific fields such as nucleation thermodynamics and heat transfer, fluid dynamics, surface chemistry, and surface nanoengineering. Here we discuss key aspects and findings related to the physics of ice formation on surfaces and show how such knowledge could be employed to rationally develop surfaces with extreme resistance to icing (extraordinary icephobicity). Although superhydrophobic surfaces with micro-, nano-, or (often biomimetic) hierarchical roughnesses have shown in laboratory settings (under certain conditions) excellent repellency and low adhesion to water down to temperatures near or below the freezing point, extreme icephobicity necessitates additional important functionalities. Other approaches, such as lubricant-impregnated surfaces, exhibit both advantages and serious limitations with respect to icing. In all, a clear path toward passive surfaces with extreme resistance to ice formation remains a challenge, but it is one well worth undertaking. Equally important to potential applications is scalable surface manufacturing and the ability of icephobic surfaces to perform reliably and sustainably outside the laboratory under adverse conditions. Surfaces should possess mechanical and chemical stability, and they should be thermally resilient. Such issues and related research directions are also addressed in this article. PMID:25346213

  8. Converting bulk sugars into prebiotics: semi-rational design of a transglucosylase with controlled selectivity.

    PubMed

    Verhaeghe, Tom; De Winter, Karel; Berland, Magali; De Vreese, Rob; D'hooghe, Matthias; Offmann, Bernard; Desmet, Tom

    2016-03-01

    Despite the growing importance of prebiotics in nutrition and gastroenterology, their structural variety is currently still very limited. The lack of straightforward procedures to gain new products in sufficient amounts often hampers application testing and further development. Although the enzyme sucrose phosphorylase can be used to produce the rare disaccharide kojibiose (α-1,2-glucobiose) from the bulk sugars sucrose and glucose, the target compound is only a side product that is difficult to isolate. Accordingly, for this biocatalyst to become economically attractive, the formation of other glucobioses should be avoided and therefore we applied semi-rational mutagenesis and low-throughput screening, which resulted in a double mutant (L341I_Q345S) with a selectivity of 95% for kojibiose. That way, an efficient and scalable production process with a yield of 74% could be established, and with a simple yeast treatment and crystallization step over a hundred grams of highly pure kojibiose (>99.5%) was obtained. PMID:26858011

  9. Activity improvement of a Kluyveromyces lactis aldo-keto reductase KlAKR via rational design.

    PubMed

    Luo, Xi; Wang, Ya-Jun; Shen, Wei; Zheng, Yu-Guo

    2016-04-20

    Optically pure t-butyl 6-cyano-(3R, 5R)-dihydroxyhexanoate ((R)-1b) is the key chiral precursor for atorvastatin calcium, the most widely used cholesterol-lowering drug. Wild-type aldo-keto reductase KlAKR from Kluyveromyces lactis has ideal diastereoselectivity toward t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate (1a, dep>99.5%) but poor activity. A rational engineering was used to improve the KlAKR activity. Based on homology modeling and molecular docking, two amino acid residues (295 and 296) were selected as mutation sites, and two rounds of site-saturation mutagenesis were performed. Among the mutants, KlAKR-Y295W/W296L exhibited the highest catalytic efficiency (kcat/Km) toward 1a up to 12.37s(-1)mM(-1), which was 11.25-fold higher than that of wild-type KlAKR. Moreover, the majority of mutations have no negative impact on stereoselectivity. Using KlAKR-Y295W/W296L coupled with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for cofactor regeneration, (R)-1b was accumulated up to 162.7mM with dep value above 99.5%. KlAKR-Y295W/W296L represents a robust tool for (R)-1b synthesis. PMID:26959479

  10. Disentangling electron tunneling and protein dynamics of cytochrome c through a rationally designed surface mutation.

    PubMed

    Alvarez-Paggi, Damián; Meister, Wiebke; Kuhlmann, Uwe; Weidinger, Inez; Tenger, Katalin; Zimányi, László; Rákhely, Gábor; Hildebrandt, Peter; Murgida, Daniel H

    2013-05-23

    Nonexponential distance dependence of the apparent electron-transfer (ET) rate has been reported for a variety of redox proteins immobilized on biocompatible electrodes, thus posing a physicochemical challenge of possible physiological relevance. We have recently proposed that this behavior may arise not only from the structural and dynamical complexity of the redox proteins but also from their interplay with strong electric fields present in the experimental setups and in vivo (J. Am Chem. Soc. 2010, 132, 5769-5778). Therefore, protein dynamics are finely controlled by the energetics of both specific contacts and the interaction between the protein's dipole moment and the interfacial electric fields. In turn, protein dynamics may govern electron-transfer kinetics through reorientation from low to high donor-acceptor electronic coupling orientations. Here we present a combined computational and experimental study of WT cytochrome c and the surface mutant K87C adsorbed on electrodes coated with self-assembled monolayers (SAMs) of varying thickness (i.e., variable strength of the interfacial electric field). Replacement of the positively charged K87 by a neutral amino acid allowed us to disentangle protein dynamics and electron tunneling from the reaction kinetics and to rationalize the anomalous distance dependence in terms of (at least) two populations of distinct average electronic couplings. Thus, it was possible to recover the exponential distance dependence expected from ET theory. These results pave the way for gaining further insight into the parameters that control protein electron transfer. PMID:23611698