NS5B

About: NS5B is a research topic. Over the lifetime, 1314 publications have been published within this topic receiving 59534 citations.

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

Abstract: The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women

Abstract: Objectives: Hepatitis C virus (HCV) non-nucleoside inhibitors (NNIs) target the viral RNA-dependent RNA polymerase encoded by the NS5B gene. Several NNIs share a similar allosteric binding site, and their antiviral efficacy is attenuated by a cysteine-to-tyrosine mutation at amino acid 316 (C316Y). In the current study, we assessed NS5B resistance mutations in treatment-naive individuals from a prospective natural history study of viral infections in women. Methods: Partial NS5B sequences from HCV-positive women were amplified by RT‐PCR. Additionally, subcloning was performed to evaluate intrapatient variability in selected samples. Results: HCV NS5B genotypes were 45 genotype 1a (57.0%), 11 genotype 1b (13.9%), 5 genotype 2a (6.3%), 3 genotype 2b (3.8%), 9 genotype 3a (11.4%) and 6 genotype 4a (7.6%). One HCV genotype 1a-infected patient was found to have the C316Y mutation (1.3%). Clonal analysis further revealed that all NS5B sequences from this individual—representing three serum samples collected 4 years apart— contained the C316Y mutation. In contrast, the S282T resistance mutation was not found in any samples. Conclusions: The C316Y polymerase resistance mutation was found in 1.3% of samples from HCVinfected women. The presence of this mutation over time suggests significant replicative fitness of this variant and has implications for development of new specifically targeted antiviral therapies against HCV (STAT-C) targeting this region.

Natural variability of NS3 protease in patients infected with genotype 4 hepatitis C virus (HCV): implications for antiviral treatment using specifically targeted antiviral therapy for HCV.

Abstract: To analyze the genetic diversity of the NS3 gene in patients infected with hepatitis C virus (HCV) genotype 4 (HCV-4) and to assess the possible effects of the gene polymorphism (or variability) on drug susceptibility, 43 NS3 gene sequences were determined for 53 selected patients with HCV-4 infection. NS3 sequencing, like NS5B sequencing, allowed correct subtype determination. Most residues that were located within the catalytic triad or the NS4-binding region or that were involved in metal binding were highly conserved and identical to those found in HCV genotype 1. Compared with HCV genotype 1, all HCV-4 NS3 protein presented V36L and C16T residue changes that could potentially reduce antiprotease activity. The efficacy of antiprotease in HCV-4-infected patients remains to be proven in large clinical trials.