ArticleAntimicrobial agents and chemotherapy2011
Mechanistic characterization of GS-9190 (Tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase.
Article in Antimicrobial agents and chemotherapy, 2011. 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, 90 citations in OpenAlex.
- Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein.Antimicrobial agents and chemotherapy · 2016Trial
- Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2014Trial
- Characterization of Hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885.Antimicrobial agents and chemotherapy · 2013Trial
- Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase.Antimicrobial agents and chemotherapy · 2013Trial
- First-in-human study of the pharmacokinetics and antiviral activity of IDX375, a novel nonnucleoside hepatitis C virus polymerase inhibitor.Antimicrobial agents and chemotherapy · 2012Trial
- Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review.Molecules (Basel, Switzerland) · 2022Review
- Non-nucleoside structured compounds with antiviral activity-past 10 years (2010-2020).European journal of medicinal chemistry · 2022Review
- Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational andJournal of chemical information and modeling · 2021Article
- Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.RSC medicinal chemistry · 2021Review
- A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19.Nature communications · 2020Article
- Antiviral Candidates for Treating Hepatitis E Virus Infection.Antimicrobial agents and chemotherapy · 2019Article
- Article
- Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification.Open forum infectious diseases · 2019Article
- Design, Synthesis, Molecular Modeling Studies and Biological Evaluation of N'-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide Derivatives as Novel Anti-HCV Agents.Iranian journal of pharmaceutical research : IJPR · 2019Article
- Nucleotide Prodrug Containing a Nonproteinogenic Amino Acid To Improve Oral Delivery of a Hepatitis C Virus Treatment.Antimicrobial agents and chemotherapy · 2018Article
- Significance of NS5B Substitutions in Genotype 1b Hepatitis C Virus Evaluated by Bioinformatics Analysis.Scientific reports · 2018Article
- The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment.Hepatology communications · 2017Article
- Current therapy for chronic hepatitis C: The role of direct-acting antivirals.Antiviral research · 2017Review
- Observational
- 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
Corrections and comments
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Authors and funding
21 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitro and has demonstrated potent antiviral activity in patients chronically infected with genotype 1 (GT1) HCV. GS-9190 exhibits reduced activity against GT2a (JFH1) subgenomic replicons and GT2a (J6/JFH1) infectious virus, suggesting that the compound's mechanism of action involves a genotype-specific viral component. To further investigate the GS-9190 mechanism of action, we utilized the susceptibility differences between GT1b and GT2a by constructing a series of replicon chimeras where combinations of 1b and 2a nonstructural proteins were encoded within the same replicon. The antiviral activities of GS-9190 against the chimeric replicons were reduced to levels comparable to that of the wild-type GT2a replicon in chimeras expressing GT2a NS5B. GT1b replicons in which the β-hairpin region (amino acids 435 to 455) was replaced by the corresponding sequence of GT2a were markedly less susceptible to GS-9190, indicating the importance of the thumb subdomain of the polymerase in this effect. Resistance selection in GT1b replicon cells identified several mutations in NS5B (C316Y, Y448H, Y452H, and C445F) that contributed to the drug resistance phenotype. Reintroduction of these mutations into wild-type replicons conferred resistance to GS-9190, with the number of NS5B mutations correlating with the degree of resistance. Analysis of GS-9190 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of GS-9190 is different from other nonnucleoside inhibitors. Collectively, these data demonstrate that GS-9190 represents a novel class of nonnucleoside polymerase inhibitors that interact with NS5B likely through involvement of the β-hairpin in the thumb subdomain.
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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.