ArticleThe Journal of biological chemistry2009
Slow binding inhibition and mechanism of resistance of non-nucleoside polymerase inhibitors of hepatitis C virus.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 91 citations in OpenAlex.
- Article
- Exploring Erythrina flavonoids as potential SARS-CoV-2 RdRp inhibitors through virtual screening, in silico ADMET evaluation, and molecular dynamics simulation studies.Scientific reports · 2025Article
- Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study.International journal of molecular sciences · 2024Article
- Geometric Deep learning Prioritization and Validation of Cannabis Phytochemicals as Anti-HCV Non-nucleoside Direct-acting Inhibitors.Biomedical engineering and computational biology · 2024Article
- Article
- Alpha-mangostin, piperine and beta-sitosterol as hepatitis C antivirus (HCV): In silico and in vitro studies.Heliyon · 2023Article
- Discovery of Terpenes as Novel HCV NS5B Polymerase Inhibitors via Molecular Docking.Pathogens (Basel, Switzerland) · 2023Article
- Discovery of Novel 3-Hydroxyquinazoline-2,4(1International journal of molecular sciences · 2022Article
- Chemistry of Protein-Phenolic Interactions Toward the Microbiota and Microbial Infections.Frontiers in nutrition · 2022Review
- Simultaneous determination of HCV genotype and NS5B resistance associated substitutions using dried serum spots from São Paulo state, Brazil.Access microbiology · 2022Article
- StackHCV: a web-based integrative machine-learning framework for large-scale identification of hepatitis C virus NS5B inhibitors.Journal of computer-aided molecular design · 2021Article
- TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.Antimicrobial agents and chemotherapy · 2020Article
- Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.Viruses · 2017Article
- Prevalence of hepatitis C virus-resistant association substitutions to direct-acting antiviral agents in treatment-naïve hepatitis C genotype 1b-infected patients in western China.Infection and drug resistance · 2017Article
- Hydrogen/Deuterium Exchange Kinetics Demonstrate Long Range Allosteric Effects of Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase.The Journal of biological chemistry · 2016Article
- Review
- The hepatitis C virus core protein can modulate RNA-dependent RNA synthesis by the 2a polymerase.Virus research · 2014Article
- Inhibition of RNA binding to hepatitis C virus RNA-dependent RNA polymerase: a new mechanism for antiviral intervention.Nucleic acids research · 2014Article
- Article
- Article
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The binding affinity of four palm and thumb site representative non-nucleoside inhibitors (NNIs) of HCV polymerase NS5B to wild-type and resistant NS5B polymerase proteins was determined, and the influence of RNA binding on NNI binding affinity was investigated. NNIs with high binding affinity potently inhibited HCV RNA polymerase activity and replicon replication. Among the compounds tested, HCV-796 showed slow binding kinetics to NS5B. The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with an equilibrium Kd of 71 +/- 2 nm. Slow binding kinetics of HCV-796 was driven by slow dissociation from NS5B with a k(off) of 4.9 +/- 0.5 x 10(-4) s(-1). NS5B bound a long, 378-nucleotide HCV RNA oligonucleotide with high affinity (Kd = 6.9 +/- 0.3 nm), whereas the binding affinity was significantly lower for a short, 21-nucleotide RNA (Kd = 155.1 +/- 16.2 nm). The formation of the NS5B-HCV RNA complex did not affect the slow binding kinetics profile and only slightly reduced NS5B binding affinity of HCV-796. The magnitude of reduction of NNI binding affinity for the NS5B proteins with various resistance mutations in the palm and thumb binding sites correlated well with resistance -fold shifts in NS5B polymerase activity and replicon assays. Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydrophobic binding pocket at the palm region of NS5B. HCV-796 interaction with the induced binding pocket on NS5B is consistent with slow binding kinetics and loss of binding affinity with mutations at amino acid position 316.
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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.