ArticleProceedings of the National Academy of Sciences of the United States of America2010
Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
101 citing papers in PubMed, 2 syntheses or guidelines pooled it, 196 citations in OpenAlex.
- KASL clinical practice guidelines: management of hepatitis C.Clinical and molecular hepatology · 2016Guideline
- KASL clinical practice guidelines: management of hepatitis C.Clinical and molecular hepatology · 2014Guideline
- Virological response and safety of 24-week telaprevir alone in Japanese patients infected with hepatitis C virus subtype 1b.Journal of viral hepatitis · 2013Trial
- Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir.Antimicrobial agents and chemotherapy · 2012Trial
- The substrate envelope strategy: Structural basis for resistance mitigation in antiviral drug design.Pharmaceutical science advances · 2026Review
- Rhomboid Proteases in Plasmodium spp. : Biology, Functional Roles, and Therapeutic Potential.Acta parasitologica · 2026Review
- A Novel Host-Based Immunotherapy for the Suppression of HBV and HCV Replication: Heat-KilledCells · 2026Article
- Covalent Inhibitors in Antimicrobial Drug Development-Beyond β-Lactams.Molecules (Basel, Switzerland) · 2026Review
- Exploring evolutionary trajectories of drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors.Nature communications · 2025Article
- Preparation of Lipophilic Derivatives ofACS omega · 2025Article
- Pathogenesis, prevention, and therapeutic advances in hepatitis B, C, and D.Virology journal · 2025Review
- Article
- Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.Viruses · 2024Article
- Article
- Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis.Nature communications · 2023Article
- Prediction and design of protease enzyme specificity using a structure-aware graph convolutional network.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Accelerating antiviral drug discovery: lessons from COVID-19.Nature reviews. Drug discovery · 2023Review
- Prediction and Design of Protease Enzyme Specificity Using a Structure-Aware Graph Convolutional Network.bioRxiv : the preprint server for biology · 2023Article
- A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach.Molecules (Basel, Switzerland) · 2023Article
41 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates.
Indexed as
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.