Article detail · 2012
The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors
- Year
- 2012
- Type
- article
Data source split
- YÖKSİS YÖKSİS article record
- YÖKSİS venue PLoS Pathogens
- Catalog match (ISSN) PLOS Pathogens
- OpenAlex OpenAlex enrichment (abstract, citations, topics)
Abstract
OpenAlex · English
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.
Topics
Citations
OpenAlex cited_by_count. Not a WoS or Scopus citation count; those sources have no separate column here.
225 citations
OpenAlex cited_by_count (cache / database)
8 publications in the local catalog that cite this work (OpenAlex reference match; not the full global list).
- Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance 2013
- Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172 2016
- Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy 2015
- Design and synthesis of new HCV NS3/4A protease inhibitors to effective against drug resistance 2025
- Design and synthesis of new HCV NS3/4A protease inhibitors to effective against drug resistance 2025
- Design and synthesis of new HCV NS3/4A protease inhibitors to effective against drug resistance 2025
- Design and synthesis of new HCV NS3/4A protease inhibitors to effective against drug resistance 2025
- Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease 2018