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

PLoS Pathogens

Djade Soumana¹  Laura M. Deveau¹  Casey Silver¹  Ayşegül Özen¹  Hong Cao¹  Akbar Ali¹  Celia A. Schiffer¹  Cihan Aydin¹  Keith P. Romano¹  Alicia Newton²  Christos J. Petropoulos²  Wei Huang² 

[1] Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Monogram Biosciences, San Francisco, California, United States of America

关键词: Proteases;    Antimicrobial resistance;    Protease inhibitors;    Crystal structure;    Hepatitis C virus;    Drug research;    development;    Hydrogen bonding;    Enzyme assays;   

DOI  :  10.1371/journal.ppat.1002832

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY