ArticleAntimicrobial agents and chemotherapy2009
Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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.
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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.
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Who cites it
23 citing papers in PubMed, 77 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
- RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.European journal of medicinal chemistry · 2021Review
- Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.RSC medicinal chemistry · 2021Review
- 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
- Review
- [Naturally occurring NS5B variants resistant to non-nucleoside or nucleoside polymerase inhibitors among treatment-naïve hepatitis C patients in south China].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2015Article
- Cross-genotypic examination of hepatitis C virus polymerase inhibitors reveals a novel mechanism of action for thumb binders.Antimicrobial agents and chemotherapy · 2014Article
- Clinical and in vitro resistance to GS-9669, a thumb site II nonnucleoside inhibitor of the hepatitis C virus NS5B polymerase.Antimicrobial agents and chemotherapy · 2014Article
- In vitro characterization of GSK2485852, a novel hepatitis C virus polymerase inhibitor.Antimicrobial agents and chemotherapy · 2013Article
- Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment.Journal of virology · 2013Article
- Preclinical characterization of JTK-853, a novel nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.Antimicrobial agents and chemotherapy · 2012Article
- Characterization of resistance to the nonnucleoside NS5B inhibitor filibuvir in hepatitis C virus-infected patients.Antimicrobial agents and chemotherapy · 2012Article
- Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir.Antimicrobial agents and chemotherapy · 2012Article
- New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy.Journal of Zhejiang University. Science. B · 2012Review
- Mechanistic characterization of GS-9190 (Tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase.Antimicrobial agents and chemotherapy · 2011Article
- Antiviral drugs against hepatitis C virus.Genetic vaccines and therapy · 2011Article
- HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies.Current HIV/AIDS reports · 2011Review
- Development of novel antiviral therapies for hepatitis C virus.Virologica Sinica · 2010Review
- Article
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 microM against genotype 1 polymerases and a mean 50% effective concentration (EC(50)) of 0.075 microM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC(50) of 0.059 microM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 microM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.
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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.