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Structural Dynamics And Inhibition Of Hepatitis C Rna Dependent Rna Polymerase
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Book Synopsis Structural Dynamics and Inhibition of Hepatitis C RNA-dependent RNA Polymerase by : Jiawen Li
Download or read book Structural Dynamics and Inhibition of Hepatitis C RNA-dependent RNA Polymerase written by Jiawen Li and published by . This book was released on 2017 with total page 332 pages. Available in PDF, EPUB and Kindle. Book excerpt: Combination therapy with direct-acting antivirals including nucleotide analogs (NAs) and non-nucleoside inhibitors (NNIs) targeting the RNA-dependent RNA polymerase NS5B have seen recent advancements and have dramatically improved the potency of Hepatitis C Virus (HCV) treatment. However, other than the identification of their site of action, very little is known about the inhibition mechanisms of these clinically relevant drugs. Lately, our lab has developed robust kinetic assays to characterize de novo RNA synthesis catalyzed by HCV NS5B, and then applied the assays to examine the mechanistic basis of action and to establish kinetic parameters governing the efficacy of various clinically relevant NAs and NNIs provided by three pharmaceutical companies (Gilead Sciences, Inc., Alios Biopharma and AbbVie Inc.). In addition, to probe the enzyme conformational dynamics of NS5B from de no initiation to elongation in the presence and absence of allosteric inhibitors, we collaborated with Dr. Patrick Wintrode on Hydrogen Deuterium exchange kinetics and Dr. Serdal Kirmizialtin on Molecular Dynamics simulations. Together, our collaborative efforts have provided a fundamental understanding of RNA-dependent RNA replication catalyzed by the HCV viral polymerase NS5B, and have established the inhibition mechanisms of anti-HCV agents. This work offers significant insights to aid the development of more effective drugs against HCV.
Book Synopsis De Novo Initiated RNA Synthesis by the Hepatitis C Virus RNA-dependent RNA Polymerase by : Sreedhar Reddy Chinnaswamy
Download or read book De Novo Initiated RNA Synthesis by the Hepatitis C Virus RNA-dependent RNA Polymerase written by Sreedhar Reddy Chinnaswamy and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis C Virus (HCV) is a positive-strand RNA virus that has infected more than 3% of the world population. Chronic infections by the virus lead to cirrhosis and hepatocellular carcinoma. HCV is currently the leading cause for liver transplantation in the US. The nonstructural protein NS5B of HCV is the RNA-dependent RNA polymerase (RdRp) that replicates the viral RNA on host derived membranous structures. Structurally NS5B has the characteristic fingers, thumb and palm domains seen in all polymerase proteins. However, extensive interactions between the fingers and thumb domains completely encircle the active site of NS5B as seen in solved X-ray diffraction crystal structures. These interactions are primarily mediated by a short (35 residues) flexible loop called the Delta 1 loop. NS5B produced from heterologous systems can initiate RNA synthesis by a de novo initiation mechanism from 3'ends of RNA templates or can also extend from 3'ends of primers that are annealed stably to a template RNA in biochemical assays. The closed conformation of NS5B as per X-ray crystal structures can only accommodate a ssRNA but not a dsRNA, hence necessitating a conformational change between de novo initiation and elongation. The details of these conformational changes are not known and will prove to be important to design potent polymerase inhibitors. The study performed for this dissertation focused on the conformational requirements of NS5B during de novo initiation and primer extension (or elongation). Biochemical assays utilizing template RNAs that can lead to both de novo initiation and primer extension products were utilized, and a systematic mutational analysis of the template channel of the RdRp was performed. Mutants W397A and H428A were identified that showed only primer extension but no de novo initiation. Structural analysis of NS5B suggested that these residues were important contact points in the Delta 1 loop and thumb domain interactions. A deletion mutant, m26-30 with a five amino acid deletion at the apex of the Delta 1 loop also failed in de novo initiation but not primer extension reactions. Biophysical and gel shift assays showed that m26-30 was in a more open conformation than the WT enzyme. Furthermore, oligomerization of NS5B was demonstrated and its role in RNA synthesis was examined. It was found that the de novo initiation competent conformation of NS5B is maintained by oligomeric contacts between individual subunits, likely by stabilizing the Delta 1 loop and thumb domain interactions. Mutations disrupting the Delta 1 loop and thumb domain interactions as well as those in the allosteric GTP binding site induced conformational changes in the protein partially explaining the defect in de novo initiation activity in enzymes carrying those mutations. These results not only contribute to the overall mechanism of RNA synthesis in viral RdRps but also open new avenues for developing HCV polymerase inhibitors.
Book Synopsis Mechanisms of Action and Resistance to Novel Inhibitors of the Hepatitis C Virus RNA -dependent RNA Polymerase by : Anupriya Kulkarni
Download or read book Mechanisms of Action and Resistance to Novel Inhibitors of the Hepatitis C Virus RNA -dependent RNA Polymerase written by Anupriya Kulkarni and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The hepatitis C virus (HCV) is a positive-sense RNA virus that encodes a non-structural protein, NS5B, which is an RNA-dependent RNA polymerase. NS5B is required for replication of the viral genome, making it an attractive target for antiviral drug development efforts. NS5B inhibitors are classified into two major categories: nucleoside inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs bind to the enzyme active site and compete with the natural NTP for incorporation. In contrast, NNIs bind away from the active site and inhibit the polymerase activity allosterically, specifically during initiation of RNA synthesis by introducing conformational changes in the polymerase.The NS5B polymerase lacks proofreading ability, which results in a high rate of mutations during replication. This error prone nature of the HCV polymerase has given rise to a number of variants of the virus which are classified into different genotypes and subgenotypes. Different HCV genotypes show variations in drug susceptibility, particularly to NNIs, which limits their clinical utility. At least four distinct binding sites for NNIs have been identified on the NS5B protein and these binding sites are not necessarily conserved across the genotypes. This provides a possible explanation for the observed variations in drug susceptibility. As part of the first study described in this thesis, we tested the inhibitory activity of acyl pyrrolidine and 1,5-benzodiazepine against purified NS5B enzymes that represent the major HCV genotypes. We identified natural amino acid substitutions that contribute to resistance to the NNIs. In the second study described herein, we turned our attention to the mechanisms of action and resistance to NIs, with focus on sofosbuvir, which is part of the current standard of care in anti-HCV therapy. Previous crystallographic data of HCV NS5B in complex with an RNA primer-template has provided important information on the protein-nucleic acid interface during the elongation process. The structure points to specific interactions between residues of the nucleic acid binding channel and the 2'-hydroxyl group of the bound RNA substrate. Using templates with strategically engineered DNA-like residues, we examined the role of the 2'-hydroxyl group of the template strand in nucleotide incorporation. Our biochemical findings suggest that this 2'-hydroxyl group plays an essential role in establishing resistance to NIs, and this process may be mediated by the signature S282T mutation, which is been known to cause resistance to sofosbuvir. In the third study, we further evaluated the efficacy of novel NIs against known NI resistance-conferring mutations in NS5B. The compounds 2'F-2'-C-Me-UTP (sofosbuvir), 2'-C-Me-2'-NH2-UTP, 2'-C-Me-UTP and 2'-C-Me-(1-Thio)UTP, which were modified derivatives of sofosbuvir, were tested against mutations S282T, L159F, C316N and L320F. It was observed that S282T showed resistance to all the modified compounds. Mutations L159F, C316N and L320F showed sensitivity towards 2'-C-Me-UTP. WT NS5B, L159F, C316N and L320F showed increased IC50 values towards 2'-C-Me-2'-NH2-UTP and 2'-C-Me-(1-Thio) UTP suggesting that addition of NH2 and Thio groups do not increase the efficacy of the compounds.Overall, these studies provide a more detailed understanding of mechanisms of action and resistance to Nucleoside and Non-nucleoside inhibitors of the HCV polymerase. Our findings offer new avenues in current efforts to develop new viral polymerase inhibitors. " --
Author :Katsuhiko S. Murakami Publisher :Springer Science & Business Media ISBN 13 :3642397964 Total Pages :342 pages Book Rating :4.6/5 (423 download)
Book Synopsis Nucleic Acid Polymerases by : Katsuhiko S. Murakami
Download or read book Nucleic Acid Polymerases written by Katsuhiko S. Murakami and published by Springer Science & Business Media. This book was released on 2013-10-22 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a review of the multitude of nucleic acid polymerases, including DNA and RNA polymerases from Archea, Bacteria and Eukaryota, mitochondrial and viral polymerases, and other specialized polymerases such as telomerase, template-independent terminal nucleotidyl transferase and RNA self-replication ribozyme. Although many books cover several different types of polymerases, no book so far has attempted to catalog all nucleic acid polymerases. The goal of this book is to be the top reference work for postgraduate students, postdocs, and principle investigators who study polymerases of all varieties. In other words, this book is for polymerase fans by polymerase fans. Nucleic acid polymerases play a fundamental role in genome replication, maintenance, gene expression and regulation. Throughout evolution these enzymes have been pivotal in transforming life towards RNA self-replicating systems as well as into more stable DNA genomes. These enzymes are generally extremely efficient and accurate in RNA transcription and DNA replication and share common kinetic and structural features. How catalysis can be so amazingly fast without loss of specificity is a question that has intrigued researchers for over 60 years. Certain specialized polymerases that play a critical role in cellular metabolism are used for diverse biotechnological applications and are therefore an essential tool for research.
Book Synopsis Viral Polymerases by : Satya Prakash Gupta
Download or read book Viral Polymerases written by Satya Prakash Gupta and published by Academic Press. This book was released on 2018-10-29 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viral Polymerases: Structures, Functions and Roles as Antiviral Drug Targets presents in-depth study information on the structure and functions of polymerases and their roles in the lifecycle of viruses, and as drug targets. Viral polymerases constitute a vital component in the lifecycle of many viruses, such as human immunodeficiency virus (HIV), hepatitis viruses, influenza virus, and several others. They are essentially required for the replication of viruses. Thus, the polymerases that can be found in viruses (called viral polymerases) represent favorable targets for the design and development of antiviral drugs. Provides comprehensive, state-of-the-art coverage on virus infections, the virus lifecycle, and mechanisms of polymerase inhibition Analyzes the structure-activity relationships of inhibitors of each viral polymerase Presents a consistent and comprehensive coverage of all aspects of viral polymerases, including structure, function and their role as antiviral drug targets
Book Synopsis Virus Protein and Nucleoprotein Complexes by : J. Robin Harris
Download or read book Virus Protein and Nucleoprotein Complexes written by J. Robin Harris and published by Springer. This book was released on 2018-06-13 with total page 443 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Subcellular Biochemistry series has recently embarked upon an almost encyclopaedic coverage of topics relating to the structure and function of macromolecular complexes (Volumes 82, 83 and 87). The present multi-author text covers numerous aspects of current research into molecular virology, with emphasis upon viral protein and nucleoprotein structure and function. Structural data from cryo-electron microscopy and X-ray crystallography is displayed throughout the book. The 17 chapters in the book cover diverse interesting topics, all currently under investigation, contributed by authors who are active actively involved in present-day research. Whilst structural aspects predominate, there is much consideration of the structure-function relationship. In addition, the book correlates with and extends from Volume 68 of the series “Structure and Physics of Viruses: An Integrated Textbook”. This book is directed primarily at professionals that work in the broad field of Structural Biology and will be of particular interest to Structural Virologists. The editors, David Bhella and Robin Harris, have much experience in virology and protein structure, respectively. Dr Bhella is Director of the Scottish Macromolecular Imaging Centre. Professor Robin Harris is the long-standing Series Editor of the Subcellular Biochemistry series. He has edited and contributed to several books in the series.
Book Synopsis Molecular Biology of Picornaviruses by : Bert L. Semler
Download or read book Molecular Biology of Picornaviruses written by Bert L. Semler and published by . This book was released on 2002 with total page 560 pages. Available in PDF, EPUB and Kindle. Book excerpt: -- Up-to-date and in-depth analysis.
Book Synopsis Viral Proteases and Their Inhibitors by : Satya Prakash Gupta
Download or read book Viral Proteases and Their Inhibitors written by Satya Prakash Gupta and published by Academic Press. This book was released on 2017-07-03 with total page 518 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viral Proteases and Their Inhibitors provides a thorough examination of viral proteases from their molecular components, to therapeutic applications. As information on three dimensional structures and biological functions of these viral proteases become known, unexpected protein folds and unique mechanisms of proteolysis are realized. This book investigates how this facilitates the design and development of potent antiviral agents used against life-threatening viruses. Users will find descriptions of each virus that detail the structure and function of viral proteases, discuss the design and development of inhibitors, and analyze the structure-activity relationships of inhibitors. This book is ideal biochemists, virologists and those working on antiviral agents. Provides comprehensive, state-of-the-art coverage of virus infections, the virus lifecycle, and mechanisms of protease inhibition Analyzes structure-activity relationships of inhibitors of each viral protease Presents an in-depth view of the structure and function of viral proteases
Book Synopsis Dengue and Zika: Control and Antiviral Treatment Strategies by : Rolf Hilgenfeld
Download or read book Dengue and Zika: Control and Antiviral Treatment Strategies written by Rolf Hilgenfeld and published by Springer. This book was released on 2018-05-29 with total page 375 pages. Available in PDF, EPUB and Kindle. Book excerpt: This contributed volume contains 25 chapters from leading international scientists working on dengue and Zika viruses, who came together in Praia do Tofo in Mozambique to discuss the latest developments in the fields of epidemiology, pathogenesis, structural virology, immunology, antiviral drug discovery and development, vaccine efficacy, and mosquito control programs. The meeting venue offered an opportunity to discuss current research on these flaviviruses in an idyllic setting, and also to develop first-hand appreciation of the issues in infectious diseases facing developing countries and of the research gaps in Africa. For readers, who should include basic and clinical researchers in the field and public health professionals, the chapters are organized to provide a comprehensive overview of the various topics in current dengue and Zika virus research. A unique feature of the proceedings of this meeting is the inclusion of the discussions that took place following presentations. These have been transcribed and appended to the end of the relevant chapters, and they form the “salt in the soup” of this book.
Book Synopsis Recoding: Expansion of Decoding Rules Enriches Gene Expression by : John F. Atkins
Download or read book Recoding: Expansion of Decoding Rules Enriches Gene Expression written by John F. Atkins and published by Springer Science & Business Media. This book was released on 2010-03-10 with total page 473 pages. Available in PDF, EPUB and Kindle. Book excerpt: The literature on recoding is scattered, so this superb book ?lls a need by prov- ing up-to-date, comprehensive, authoritative reviews of the many kinds of recoding phenomena. Between 1961 and 1966 my colleagues and I deciphered the genetic code in Escherichia coli and showed that the genetic code is the same in E. coli, Xenopus laevis, and guinea pig tissues. These results showed that the code has been c- served during evolution and strongly suggested that the code appeared very early during biological evolution, that all forms of life on earth descended from a c- mon ancestor, and thus that all forms of life on this planet are related to one another. The problem of biological time was solved by encoding information in DNA and retrieving the information for each new generation, for it is easier to make a new organism than it is to repair an aging, malfunctioning one. Subsequently, small modi?cations of the standard genetic code were found in certain organisms and in mitochondria. Mitochondrial DNA only encodes about 10–13 proteins, so some modi?cations of the genetic code are tolerated that pr- ably would be lethal if applied to the thousands of kinds of proteins encoded by genomic DNA.
Book Synopsis Molecular Virology by : Susanne Modrow
Download or read book Molecular Virology written by Susanne Modrow and published by Springer. This book was released on 2013-09-18 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The book gives a comprehensive overview on the knowledge of virus infection relevant for humans and animals. For each virus family the molecular details of the virus particle and the viral replication cycle are described. In the case of virus types with relevance for human and/or animal health the data on molecular biology, genetics and virus-cell interaction are combined with those concerning, pathogenesis, epidemiology, clinics, prevention and therapy.
Book Synopsis Protein Structure Prediction by : Daisuke Kihara
Download or read book Protein Structure Prediction written by Daisuke Kihara and published by Humana. This book was released on 2021-07-18 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: This thorough new edition explores web servers and software for protein structure prediction and modeling that are freely available to the academic community. Taking into account the numerous advances in the computational protein structure prediction/modeling field, the book includes residue-contact prediction via deep learning, a wide variety of protein docking models, as well as cryo-electron microscopy (cryo-EM) techniques. Written by renowned experts in the field and for the highly successful Methods in Molecular Biology series, chapters include the kind of key detail and implementation advice necessary for researchers to achieve optimal results in their own work. Authoritative and fully updated, Protein Structure Prediction, Fourth Edition is a practical and immediately useful guide for biology researchers working toward modeling protein structures./div/div/div/div/div/div/div/div/div/div/div/div/div/div/div/div/divdiv
Book Synopsis Hepatitis C Virus I by : Tatsuo Miyamura
Download or read book Hepatitis C Virus I written by Tatsuo Miyamura and published by Springer. This book was released on 2016-10-28 with total page 361 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume is composed of chapters that review important fundamental aspects of HCV biology and disease pathogenesis including, for example, the discovery and identification of the HCV genome, early virus-cell interactions including identification of various cellular receptors, HCV gene expression studied using the HCV replicon system, identification and characterization of HCV structural- and non-structural HCV proteins, HCV replication in cultured cells, and host factors involved in viral replication. This volume also contains chapters dealing with immunity to HCV infection and pathogenesis. This is particularly important in understanding hepatitis C because HCV infection alone is not cell lytic. Mechanisms underlying the persistent nature of HCV infection are also discussed in these chapters. Many of the authors published articles that were listed among the “top 10 papers” published in the 24 years since HCV was discovered in 1989. Their citations are above 1,000 (Web of Science). The authors describe the background and significance of their contributions to the field in the context of findings from other research groups.
Book Synopsis Hepatitis: New Insights for the Healthcare Professional: 2013 Edition by :
Download or read book Hepatitis: New Insights for the Healthcare Professional: 2013 Edition written by and published by ScholarlyEditions. This book was released on 2013-07-22 with total page 507 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis: New Insights for the Healthcare Professional: 2013 Edition is a ScholarlyEditions™ book that delivers timely, authoritative, and comprehensive information about Diagnosis and Screening. The editors have built Hepatitis: New Insights for the Healthcare Professional: 2013 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Diagnosis and Screening in this book to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Hepatitis: New Insights for the Healthcare Professional: 2013 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Book Synopsis Protein-nucleic Acid Interaction by : Wolfram Saenger
Download or read book Protein-nucleic Acid Interaction written by Wolfram Saenger and published by . This book was released on 1989 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume contains a series of essays which describe a range of problems in the field of nucleic-acid interactions, investigated by a variety of techniques. An introductory chapter on DNA-protein interactions in the regulation of gene expression is followed by papers on selected model systems.
Book Synopsis Structural Biology for Virus Research by : Akio Adachi
Download or read book Structural Biology for Virus Research written by Akio Adachi and published by Frontiers Media SA. This book was released on with total page 104 pages. Available in PDF, EPUB and Kindle. Book excerpt: Viruses are absolutely and strictly dependent on target host cells for their replication. However, they have their own unique strategies at each replication step from the entry into cells, transcription, translation, assembly of viral genome/proteins, and up to the release of progeny virions from cells. We virologists have to understand these complex biological interactions between viruses and host cells. Importantly, extensive studies based on bio-structural technology have revealed in succession the detailed and bottom line mechanisms of viral replication processes otherwise impossible. We now know the highly dynamic nature of viral genome/proteins, and are impressed by their ingeniously organized functionality in hostile host environments. For characterization of viruses as a unique genetic entity and pathogenic agent, it has been critical to investigate thoroughly the individual viral components and host factors involved in the virus replication cycle. Because many viral and cellular factors essential for viral replication and pathogenicity have been newly discovered through the efforts of virologists, the necessity of contribution to the progress of virology by the structural biology is now greatly increasing. To fully understand precise mechanisms underlying the functional interaction of viral and host molecules, needless to say, it is crucially required to have their structural information. We need to know molecular details of the nucleic acids, proteins, and interacting molecules. The information indispensable for understanding certain biological phenomena may only be provided by high-resolution three-dimensional structures. Of note, a number of anti-viral drugs have been generated based on the structural information. The interacting interfaces between virus and host components, which are important for viral replication, can be potent targets for anti-viral drugs. Their structural characterization would lead to designing rigid anti-viral drugs and/or vaccines. In this Research Topic, we wish to summarize and review what the structural biology has accomplished so far to resolve the important virological issues. We also wish to describe the perspective of the structural biology for the future virology. Finally, the presentation of ongoing original works is greatly encouraged.
Book Synopsis Antimicrobial Drug Resistance by : Douglas Mayers
Download or read book Antimicrobial Drug Resistance written by Douglas Mayers and published by Springer Science & Business Media. This book was released on 2009-07-06 with total page 673 pages. Available in PDF, EPUB and Kindle. Book excerpt: This ? rst edition of Antimicrobial Drug Resistance grew out of a desire by the editors and authors to have a comprehensive resource of information on antimicrobial drug resistance that encompassed the current information available for bacteria, fungi, protozoa and viruses. We believe that this information will be of value to clinicians, epidemiologists, microbiologists, virologists, parasitologists, public health authorities, medical students and fellows in training. We have endeavored to provide this information in a style which would be accessible to the broad community of persons who are concerned with the impact of drug resistance in our cl- ics and across the broader global communities. Antimicrobial Drug Resistance is divided into Volume 1 which has sections covering a general overview of drug resistance and mechanisms of drug resistance ? rst for classes of drugs and then by individual microbial agents including bacteria, fungi, protozoa and viruses. Volume 2 addresses clinical, epidemiologic and public health aspects of drug resistance along with an overview of the conduct and interpretation of speci? c drug resistance assays. Together, these two volumes offer a comprehensive source of information on drug resistance issues by the experts in each topic.
