ArticleJournal of virology2010
1a/1b subtype profiling of nonnucleoside polymerase inhibitors of hepatitis C virus.
Article in Journal of virology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 38 citations in OpenAlex.
- Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845.Virology journal · 2017Article
- A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening.The Journal of biological chemistry · 2016Article
- A highly conserved G-rich consensus sequence in hepatitis C virus core gene represents a new anti-hepatitis C target.Science advances · 2016Article
- Review
- Review
- Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase.Biophysical journal · 2015Article
- Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods.Bioorganic & medicinal chemistry · 2013Article
- Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase.Proteins · 2013Article
- TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage.Antimicrobial agents and chemotherapy · 2012Article
- Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.Antimicrobial agents and chemotherapy · 2012Article
- High-throughput screening and rapid inhibitor triage using an infectious chimeric Hepatitis C virus.PloS one · 2012Article
- Anti-HCV drugs in the pipeline.Current opinion in virology · 2011Review
- Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase.Antimicrobial agents and chemotherapy · 2011Article
- Hepatitis C virus genotyping using an oligonucleotide microarray based on the NS5B sequence.Journal of clinical microbiology · 2010Article
- New antiviral therapies for chronic hepatitis C.Hepatology international · 2010Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
22 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor- and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.
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