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Structure And Functional Studies Of The Hepatitis C Virus Ns5b Gene Product The Rna Dependent Rna Polymerase
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Book Synopsis Structure and Functional Studies of the Hepatitis C Virus NS5B Gene Product - the RNA Dependent RNA Polymerase by : Damien O'Farrell
Download or read book Structure and Functional Studies of the Hepatitis C Virus NS5B Gene Product - the RNA Dependent RNA Polymerase written by Damien O'Farrell and published by . This book was released on 2002 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis In Vitro Biochemical Studies of NS5B, the HCV RNA Dependant RNA Polymerase by : Salvatore Marshall Cilia
Download or read book In Vitro Biochemical Studies of NS5B, the HCV RNA Dependant RNA Polymerase written by Salvatore Marshall Cilia and published by . This book was released on 2009 with total page 310 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis In Vitro Studies of the Hepatitis C Virus (HCV) RNA Dependent RNA Polymerase NS5B by : Elizabeth Margarita Quezada
Download or read book In Vitro Studies of the Hepatitis C Virus (HCV) RNA Dependent RNA Polymerase NS5B written by Elizabeth Margarita Quezada and published by . This book was released on 2008 with total page 440 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Study of RNA Synthesis of Hepatitis C Virus in Vitro and in Cells of Hepatocarcinoma by : Neveen Ahmed El Sayed
Download or read book Study of RNA Synthesis of Hepatitis C Virus in Vitro and in Cells of Hepatocarcinoma written by Neveen Ahmed El Sayed and published by . This book was released on 2011 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The hepatitis C virus (HCV) NS5B protein displays a RNA-dependent RNA polymerase activity essential for replication of the viral RNA genome. This replication involves the synthesis of a replication intermediate of negative polarity. In vitro and likely in vivo, the NS5B initiates RNA synthesis by a de novo mechanism which requires specific interactions between the polymerase and viral RNA elements. In the first part of results, we described a combined structural and functional analysis of HCV-NS5B to study the role of a C-terminal segment (termed linker) and of GTP in RNA synthesis. Our results demonstrated that high GTP concentrations are necessary for the transition from the initiation to the elongation of RNA synthesis, and that linker mutations at position S556 did not modify the GTP requirement of NS5B for this transition. However, the initiation of RNA synthesis was greatly enhanced by a S556K mutation. These results together with a structural analysis point to the direct involvement of the linker in the de novo initiation of RNA synthesis. In the second and third parts of results, we studied the role of RNA elements in RNA synthesis. We demonstrated that the SL-E1 stem-loop formed by nucleotides 177-222 from the 3'-end of the HCV (-) RNA is important for RNA synthesis both in vitro by the recombinant NS5B and in Huh7 cells by HCV replication complex (RC). We also showed that SL-E1 is involved in initiation of RNA synthesis, at least in vitro. Then we studied the role of other viral RNA elements in core coding sequences (SLV and SLVI stem loops) and the involvement of the microRNA miR122 in RNA translation and RNA synthesis. For SLV and SLVI, our data did not show any clear role of these core-coding sequences or of their complement in the (-) RNA in RNA synthesis both in vitro by the recombinant NS5B and in cell culture by HCV-RC. We confirmed their negative effect on HCV-IRES translation through long range RNA-RNA interaction between SL-VI sequences and the 5'UTR and demonstrated that miR122 cannot disrupted this interaction and switches the region to an open conformation. Conversely, our data indicated that the SL-VI domain can counteract the negative effect of the interaction between the domain III of IRES and the 5BSL3.2 stem loop localized at the 3'end of the genome. These results point to the complexity of RNA/RNA and RNA/proteins interactions in the HCV replication cycle.
Book Synopsis Investigation of the Hepatitis C Virus RNA Polymerase NS5B in Solution by Nuclear Magnetic Resonance and Its Interaction with Intrinsically Disordered Domain 2 of the NS5A Protein by : Luíza Mamigonian Bessa
Download or read book Investigation of the Hepatitis C Virus RNA Polymerase NS5B in Solution by Nuclear Magnetic Resonance and Its Interaction with Intrinsically Disordered Domain 2 of the NS5A Protein written by Luíza Mamigonian Bessa and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: NS5B is the hepatitis C virus (HCV) RNA-dependent RNA polymerase. This protein has been extensively studied by X-ray crystallography and shows an organization in three subdomains called fingers, palm and thumb. Whereas static crystallographic data are abundant, structural studies of this protein in solution are limited. Nuclear magnetic resonance (NMR) spectroscopy was used to study the 65 kDa NS5B in solution as well as its interaction with binding partners. It was characterized using selective isotopic labeling of isoleucine side-chain methyl groups, which gives rise to a simplified NMR spectrum with an improved signal-to-noise ratio. This characterization confirmed the presence of particular dynamics in the subdomains, especially in the thumb, as well as long-range effects that are transmitted through to other subdomains. Furthermore, this system was used to investigate the binding of the domain 2 of NS5A (NS5A-D2), a disordered domain of another HCV protein that has been shown to directly interact with NS5B in vitro. With paramagnetic relaxation enhancement experiments we showed that NS5A-D2 binds to NS5B via, at least, two binding sites on the thumb subdomain. As one of these sites was the binding site of allosteric inhibitor filibuvir, we characterized the binding of this small molecule to NS5B by NMR and found long-range effects of its binding throughout the polymerase. Finally, we studied the binding of a small RNA template strand to NS5B and found that both NS5A-D2 and filibuvir reduce but do not abolish the interaction between the polymerase and RNA. In sum, NMR spectroscopy was used to study dynamic properties of NS5B and its interactions with binding partners.
Book Synopsis Characterization of the Hepatitis C Virus NS5b RNA-dependent RNA Polymerase by : Megan Heather Powdrill
Download or read book Characterization of the Hepatitis C Virus NS5b RNA-dependent RNA Polymerase written by Megan Heather Powdrill and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The hepatitis C virus polymerase NS5b is required for replication of the viral genome, making it an attractive target for antiviral development. The polymerase contains no proof-reading activity and generates viral variants during replication with a high degree of genetic heterogeneity, complicating the development of effective antiviral therapies since resistance mutations are readily selected under drug pressure. A successful treatment regimen will likely require a combination therapy that can suppress the emergence of resistance. Here, we have described the mechanism of action of a novel class of polymerase active site inhibitors, pyrophosphate analogues. We studied interactions between these compounds and NS5b in the presence of the resistance mutations G152E and P156L and have identified interactions leading to resistance. Additionally, we have combined the pyrophosphate analogues with a second class of polymerase active site inhibitors, nucleoside analogue...
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
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 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 Studies on Hepatitis Viruses by : Satya Prakash Gupta
Download or read book Studies on Hepatitis Viruses written by Satya Prakash Gupta and published by Academic Press. This book was released on 2018-06-20 with total page 244 pages. Available in PDF, EPUB and Kindle. Book excerpt: Studies on Hepatitis Viruses: Life Cycle, Structure, Functions, and Inhibition presents the latest on this systemic infection that predominantly affects the liver with inflammation that can be acute or chronic. Hepatitis viruses have been the subject of intense study in the last twenty years, with a wealth of information related to their lifecycle, structure, functions and inhibition being presented. This book compiles the most important developments and research, giving users a very useful guide on this evolving area of virology and medicinal chemistry. Provides comprehensive, state-of-the-art coverage of hepatitis virus infections, the virus' lifecycle, and mechanisms of protease inhibition Analyzes structure-activity relationships of inhibitors of viral hepatitis Presents an in-depth view of the structure and function of viral hepatitis Discusses classification, epidemiology, pathogenesis, natural history, clinical manifestations, diagnosis, complications, associated disorders and animal models
Book Synopsis Flexible Viruses by : Vladimir Uversky
Download or read book Flexible Viruses written by Vladimir Uversky and published by John Wiley & Sons. This book was released on 2012-02-07 with total page 532 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides up-to-date information on experimental and computational characterization of the structural and functional properties of viral proteins, which are widely involved in regulatory and signaling processes. With chapters by leading research groups, it features current information on the structural and functional roles of intrinsic disorders in viral proteomes. It systematically addresses the measles, HIV, influenza, potato virus, forest virus, bovine virus, hepatitis, and rotavirus as well as viral genomics. After analyzing the unique features of each class of viral proteins, future directions for research and disease management are presented.
Book Synopsis Determining the Molecular Origins of Allostery for the Polymerase from the Hepatitis C Virus by : Brittny C. Davis
Download or read book Determining the Molecular Origins of Allostery for the Polymerase from the Hepatitis C Virus written by Brittny C. Davis and published by . This book was released on 2015 with total page 322 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis C virus (HCV) infects 170 million people worldwide, and approximately 3-4 million people within the United States. To date, there is no cure for this disease, and 25% of individuals living with HCV contract chronic liver ailments such as cirrhosis or liver cancer. The HCV RNA polymerase (gene product NS5B) has become a drug target because of its importance in viral replication. Several small molecules have been identified that inhibit NS5B and bind outside of the active site; these are referred to as allosteric inhibitors. There are four different allosteric binding sites that have been identified, and several crystal structures of NS5B enzyme bound to various inhibitors exist. However, a mechanism of inhibition is unclear from the structural data alone and has yet to be conclusively determined. We hypothesize that one can understand the effect of allosteric inhibitors on the functional properties of NS5B by using molecular dynamics simulations to study the enzyme in a free state and bound to various inhibitors. Molecular dynamics is an optimal tool to study this problem because it can provide information about both structure and dynamics at the molecular level. By understanding the structural, dynamic, and thermodynamic changes that accompany ligand binding, we hope to determine the molecular origins of allosteric inhibition in NS5B. In the process we will gain essential information on how NS5B and other viral polymerases replicate RNA. Besides illuminating fundamental questions regarding the link between enzyme function and dynamics, this information may aid in the development of novel and more effective inhibitors for NS5B, and ultimately better treatments for HCV.
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. " --
Book Synopsis Functional Interactions of Structural and NS Proteins of Hepatitis C Virus by : Hamed Gouklani
Download or read book Functional Interactions of Structural and NS Proteins of Hepatitis C Virus written by Hamed Gouklani and published by . This book was released on 2011 with total page 362 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatitis C virus (HCV) is a small enveloped virus with a positive-sense single stranded RNA genome. Based on its molecular genetic characteristics, the virus has been classified into the Hepacivirus genus of the family Flaviviridae. HCV is one of the major causes of chronic hepatitis which can lead to liver cirrhosis and hepatocellular carcinoma. According to the recent WHO published data, 123 million individuals are infected with HCV (approximately 3% of the world's population) throughout the world. Due to its highly variable nature, HCV is classified into six major genotypes. The HCV genome encodes a single polyprotein that is cleaved to yield at least 10 mature proteins (C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B). The recently developed HCV cell culture system, based on the JFH1 strain of HCV, has provided an opportunity to study the role of the viral proteins in the complete HCV replication cycle in human hepatoma cells. How the viral proteins functionally interact during replication of HCV in cell culture is not completely understood. Passage of cell cultures transfected with HCV genomic RNA containing attenuating mutations allows for the selection of genomes with second site compensatory mutations that restore replication to wild type levels. Using this approach, the functional interactions of p7 and E2 with other viral proteins during HCV replication was investigated.A small protein of 63 amino acids, p7 is encoded at the junction of the structural and non-strucutural region. p7 is a highly hydrophobic, integral membrane protein and is classified in the viroporin family. In this thesis, it is shown that p7 is critical for production of viral particles and is implicated in a late step of particle assembly. Since the protein plays a critical role in the virus life cycle, chemical compounds that block p7 function are potential candidates for anti-viral therapy. In this thesis, a chimeric JFH1 genome that encodes the p7 protein of genotype (GT) 1b strain J4 was generated. The intergenotypic chimeric genome was nonviable in human hepatoma cells and infectious chimeric virions were only produced after cells harboring the chimeric genomes were passaged several times. To investigate the emergence of compensatory mutations in the viral proteins during cell passaging, the consensus sequences of the entire polyprotein coding regions of the wild type JFH1 and three chimeric viruses were determined. Sequence analysis revealed mutations in core, NS2, NS5A and NS5B. Reverse genetic analysis demonstrated that any one of the single mutations restored the infectivity of the defective chimeric genomes. These data suggest that there are critical genetic interactions between p7 with core, NS2, NS5A and NS5B. In addition, a stable physical interaction between p7 and NS2 is shown in a transient expression system. The HCV glycoproteins E1 and E2 are present on the surface of virions as a heterodimer that attach virions to host cell receptors and facilitate virus fusion and entry. HCV entry proceeds via attachment to glycosaminoglycans followed by binding to scavenger receptor type B class I, and the tetraspanin CD81. Recently, claudin-1 and occludin have emerged as additional receptors required for entry. E2 has a receptor binding domain (E2661RBD) that conatins three variable regions, hypervariable regions 1 (HVR1), HVR2 and the intergenotypic variable region (igVR). In this thesis, HVR1 of E2 was deleted in the context of full-length replication comptetent HCV. Deletion of HVR1 increases CD81-binding ability of the mutant and also increases its susceptibility to neutralizing antibody MAb 24. The infectivity of the HVR1 deleted virions was attenuated approximately 10-fold prior to accumulation of compensatory mutations. Sequencing of cDNA obtained from reverted virions revealed mutations in E1 (I262L) and E2 (N415D). Reverse genetic studies revealed that I262L improved the infectivity of HVR1 deleted virions 2.5 fold while N415D restored infectivity to wild type levels. These data suggest that mutations within E1 or E2 can compensate for the reduction in infectivity observed for HVR1 deleted viruses.In summary, this thesis demonstrates the importance of functional interactions between HCV proteins during virus morphogenesis and infectivity.
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 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 The Hepatitis C Viruses by : C.H. Hagedorn
Download or read book The Hepatitis C Viruses written by C.H. Hagedorn and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 386 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chronic hepatitis C is a major worldwide health problem affecting more than 170 million people. Chronic infections lead to cirrhosis and liver failure or hepatocellular cancer in many instances. This volume includes comprehensive reviews that cover much of the vast literature that has appeared since the identification of the hepatitis C virus RNA genome. It will be an invaluable collection for anyone wanting an up-to-date picture of HCV transmission, molecular virology, immune response, cellular/molecular pathogenesis, and possible avenues for developing effective new therapeutics and vaccines.
