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: Although both enzymes share common fold and function to some extent, a significant amount of unique structural and functional features have to be clearly delineated to efficiently translate drug design potential between these two essential enzymes.
Abstract: Upon the discovery of HCV, dengue virus (DENV) and other flaviviruses have served as models to unravel the biology and mechanisms at play during HCV replication. HCV research has rapidly become a well-established field. Recently, several specific anti-HCV antiviral drugs have been discovered and approved for use in the clinic. Now, the strong emergence of DENV in the world and the associated increasing burden is casting light back to dengue virology and anti-dengue drug discovery. HCV polymerase (NS5B) is a prime target in antiviral therapies, and the analogous DENV polymerase (NS5) is also becoming one. Although both enzymes share common fold and function to some extent, a significant amount of unique structural and functional features have to be clearly delineated to efficiently translate drug design potential between these two essential enzymes.
8 citations
TL;DR: In this paper, transient-state kinetics were used to understand the efficiency of inhibition for five nucleoside analogs, including CTP, UMP and sofosbuvir, and they showed that CTP analogs are readily incorporated into a growing primer by NS5B but are also efficiently excised.
8 citations
TL;DR: The need for combination therapy with HCV-specific inhibitors to avoid viral rebound of preexisting mutant HCV is suggested and developed an allele-specific real-time PCR assay capable of detecting Y448H when it was present at a level down to 0.5% within an HCV population of genotype 1a or 1b.
Abstract: The Y448H mutation in NS5B has been selected by GS-9190 as well as several benzothiadiazine hepatitis C virus (HCV) polymerase inhibitors in vitro and in vivo. However, the level and the evolution kinetics of this resistance mutation prior to and during treatment are poorly understood. In this study, we developed an allele-specific real-time PCR (AS-PCR) assay capable of detecting Y448H when it was present at a level down to 0.5% within an HCV population of genotype 1a or 1b. No Y448H mutation was detected above the assay cutoff of 0.5% in genotype 1b-infected Con-1 replicons prior to in vitro treatment. However, the proportion of replicons with the Y448H mutation rapidly increased in a dose-dependent manner upon treatment with GS-9190. After 3 days of treatment, 1.2%, 6.8%, and >50% of the replicon population expressed Y448H with the use of GS-9190 at 1, 10, and 20 times its 50% effective concentration, respectively. In addition, plasma from 65 treatment-naive HCV-infected patients (42 and 23 with genotype 1a and 1b, respectively) was tested for the presence of Y448H by AS-PCR and population sequencing. As expected, all patient samples were wild type at NS5B Y448 by population sequencing. AS-PCR results were obtained for 62/65 samples tested, with low levels of Y448H ranging from 0.5% to 3.0% detected in 5/62 (8%) treatment-naive patient samples. These findings suggest the need for combination therapy with HCV-specific inhibitors to avoid viral rebound of preexisting mutant HCV.
8 citations
TL;DR: Evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy and the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy to find out if this affects retreatment outcomes.
8 citations
TL;DR: Stable Huh-7 cell lines with HCV la non-structural proteins may be helpful for evaluating the role of HCV proteins in molecular pathogenesis, and could facilitate the development of new therapeutic drugs.
8 citations