Topic
NS5B
About: NS5B is a research topic. Over the lifetime, 1314 publications have been published within this topic receiving 59534 citations.
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TL;DR: Both nucleoside and non-nucleoside inhibitors of HCV polymerase have been identified through the innovative use of new screening tools and rational drug design, and initiation of clinical trials in the near future promises to yield exciting new information on the ability of these compounds to achieve sustained responses in suppressing HCV replication.
64 citations
TL;DR: The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients.
Abstract: Introduction. RG7128 (prodrug of PSI-6130) shows potent antiviral efficacy in patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3, with mean viral load decreases of 2.7 and 5 log 10 IU/mL, respectively, associated with 1500-mg doses twice daily after monotherapy for 2 weeks and with 1000-mg and 1500-mg doses twice daily after treatment in combination with the standard of care (SOC) for 4 weeks.Results. From 32 patients treated with RG7128 monotherapy for 2 weeks, marginal viral load rebound was observed in 3 HCV genotype 1-infected patients, whereas partial response was observed in 2 genotype 1-infected patients. From 85 patients receiving RG7128 in combination with SOC, 1 HCV genotype 1-infected patient experienced a viral rebound, and 2 genotype 3-infected patients experienced a transient rebound. Five genotype 1-infected patients had an HCV load of >1000 IU/mL at the end of 4-week treatment. No viral resistance was observed, per NS5B sequencing and phenotypic studies. PSI-6130 resistance substitution S282T needs to be present at levels of ⩾90% within a patient's quasispecies to confer low-level resistance. No evidence of S282T was found by population or clonal sequence analyses.Conclusions. The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients.
64 citations
TL;DR: Structural comparison of the NS5B proteins indicates that the activation was caused by elimination of a unique hydrophobic interaction between the three C-terminal residues and a shallowly concave pocket consisting of thumb and palm domains.
64 citations
TL;DR: The design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors are described and it is suggested that these inhibitors may bind to the NS5B active site.
64 citations
TL;DR: Results suggest that the native HCV replicase complex represents a stable and productive polymerase-RNA complex, and the allosteric non-nucleoside NS5B polymerase inhibitors are inactive against established HCV replication but may function antagonistically with the formation of a productive enzyme-template complex.
63 citations