The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors
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.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2012-07-26Keywords
Viral Nonstructural ProteinsProtease Inhibitors
Hepatitis C
Drug Resistance, Viral
Immunology and Infectious Disease
Molecular Biology
Molecular Genetics
Metadata
Show full item recordAbstract
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 siteDOI
10.1371/journal.ppat.1002832Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39539PubMed ID
22910833Notes
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.
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Link to Article in PubMedRights
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.
ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1002832