Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to t...

The hepatitis C virus (HCV) production system consists of transfecting the human hepatoma cell line Huh7 with genomic HCV RNA (JFH1). To monitor HCV replication by fluorescence microscopy, we constructed a recombinant HCV clone expressing Azami-Green (mAG), a bright green fluorescent protein, by inserting the mAG gene into the nonstructural protein 5A (NS5A) gene; the resultant clone was design...

Hepatitis C virus non-structural NS5A protein inhibits epidermal growth factor (EGF)-stimulated activation of the Ras-ERK mitogen-activated protein kinase pathway at a point upstream of Ras activation. To determine the mechanism of this inhibition, the events occurring between the EGF receptor and Ras in Huh-7 cells harbouring the HCV subgenomic replicon were investigated. It was shown that, fo...

BACKGROUND Non-structural 5A protein (NS5A) resistance-associated substitutions (RASs) have been identified in patients infected with hepatitis C virus (HCV), even prior to exposure to direct-acting antiviral agents (DAAs). Selection for these variants occurs rapidly during treatment and, in some cases, leads to antiviral treatment failure. DAAs are currently the standard of care for hepatitis ...

Introduction The role of Wnt/ β -catenin signaling pathway in HCV-associated hepatocellular carcinogenesis is still unknown. Material and methods This study aimed to perform quantitative analysis of immuno- and hybridocytochemical expression of β -catenin, E- and N-cadherins and HCV proteins (C, NS3, NS5A) in long-lasting (≥ 20 years) chronic hepatitis C (CH-C) (n = 54), hepatocellular carcin...

The NS5A protein of hepatitis C virus (HCV) plays roles in both virus genome replication and assembly. NS5A comprises three domains, of these domain I is believed to be involved exclusively in genome replication. In contrast, domains II and III are required for the production of infectious virus particles and are largely dispensable for genome replication. Domain I is highly conserved between H...

Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high sustained virologic response 12 weeks postdosing (SVR12) rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure rate (1.2%). There were no virologic f...

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studie...

Chronic hepatitis C virus (HCV) infections can be cured only in a fraction of patients treated with alpha interferon (IFN-alpha) and ribavirin combination therapy. The mechanism of the IFN-alpha response against HCV is not understood, but evidence for a role for viral nonstructural protein 5A (NS5A) in IFN resistance has been provided. To elucidate the mechanism by which NS5A and possibly other...