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    The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors

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    Authors
    Romano, Keith P.
    Ali, Akbar
    Aydin, Cihan
    Soumana, Djade
    Ozen, Aysegul
    Deveau, Laura M.
    Silver, Casey
    Cao, Hong
    Newton, Alicia
    Petropoulos, Christos J.
    Huang, Wei
    Schiffer, Celia A.
    Show allShow less
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2012-07-26
    Keywords
    Viral Nonstructural Proteins
    Protease Inhibitors
    Hepatitis C
    Drug Resistance, Viral
    Immunology and Infectious Disease
    Molecular Biology
    Molecular Genetics
    
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    Abstract
    Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors - telaprevir, danoprevir, vaniprevir and MK-5172 - in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.
    Source
    Romano KP, Ali A, Aydin C, Soumana D, Özen A, et al. (2012) The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors. PLoS Pathog 8(7): e1002832. doi:10.1371/journal.ppat.1002832. Link to article on publisher's site
    DOI
    10.1371/journal.ppat.1002832
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39539
    PubMed ID
    22910833
    Notes

    Co-author Aysegul Ozen is a student in the Biochemistry Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

    Related Resources
    Link to Article in PubMed
    Rights

    Copyright: © 2012 Romano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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