ArticleAntimicrobial agents and chemotherapy2012
Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
26 citing papers in PubMed, 59 citations in OpenAlex.
- Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor.Antimicrobial agents and chemotherapy · 2014Trial
- Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase.Antimicrobial agents and chemotherapy · 2013Trial
- Targeting of interaction between BB0323-BB0238 informs new paradigms in Lyme disease therapeutics.PLoS pathogens · 2026Article
- Geometric Deep learning Prioritization and Validation of Cannabis Phytochemicals as Anti-HCV Non-nucleoside Direct-acting Inhibitors.Biomedical engineering and computational biology · 2024Article
- Repositioning anticancer drugs as novel COVID-19 antivirals: targeting structural and functional similarities between viral proteins and cancer.Expert reviews in molecular medicine · 2022Review
- RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.European journal of medicinal chemistry · 2021Review
- RNA-dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID-19.Cancer science · 2020Review
- Global elimination of hepatitis C virus infection: Progresses and the remaining challenges.World journal of hepatology · 2017Review
- NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B.The Journal of biological chemistry · 2017Article
- Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.Viruses · 2017Article
- Current therapy for chronic hepatitis C: The role of direct-acting antivirals.Antiviral research · 2017Review
- Article
- De Novo RNA Synthesis by RNA-Dependent RNA Polymerase Activity of Telomerase Reverse Transcriptase.Molecular and cellular biology · 2016Article
- Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses.Journal of virology · 2016Article
- Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative.Antiviral chemistry & chemotherapy · 2015Article
- Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay.Antiviral research · 2015Article
- Review
- The juxtamembrane sequence of the Hepatitis C virus polymerase can affect RNA synthesis and inhibition by allosteric polymerase inhibitors.Virus genes · 2015Article
- The murine norovirus core subgenomic RNA promoter consists of a stable stem-loop that can direct accurate initiation of RNA synthesis.Journal of virology · 2015Article
- Subgenomic promoter recognition by the norovirus RNA-dependent RNA polymerases.Nucleic acids research · 2015Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Filibuvir and VX-222 are nonnucleoside inhibitors (NNIs) that bind to the thumb II allosteric pocket of the hepatitis C virus (HCV) RNA-dependent RNA polymerase. Both compounds have shown significant promise in clinical trials and, therefore, it is relevant to better understand their mechanisms of inhibition. In our study, filibuvir and VX-222 inhibited the 1b/Con1 HCV subgenomic replicon, with 50% effective concentrations (EC(50)s) of 70 nM and 5 nM, respectively. Using several RNA templates in biochemical assays, we found that both compounds preferentially inhibited primer-dependent RNA synthesis but had either no or only modest effects on de novo-initiated RNA synthesis. Filibuvir and VX-222 bind to the HCV polymerase with dissociation constants of 29 and 17 nM, respectively. Three potential resistance mutations in the thumb II pocket were analyzed for effects on inhibition by the two compounds. The M423T substitution in the RNA polymerase was at least 100-fold more resistant to filibuvir in the subgenomic replicon and in the enzymatic assays. This resistance was the result of a 250-fold loss in the binding affinity (K(d)) of the mutated enzyme to filibuvir. In contrast, the inhibitory activity of VX-222 was only modestly affected by the M423T substitution but more significantly affected by an I482L substitution.
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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.