A Refined Model of the HCV NS5A Protein Bound to Daclatasvir Explains Drug-Resistant Mutations and Activity against Divergent Genotypes

Citations Over TimeTop 10% of 2014 papers

Abstract

Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.

Related Papers

• → Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection(1999)79 cited
• → Distribution of hepatitis C virus genotypes in Jeju Island(2008)10 cited
• → Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs(2019)10 cited
• → Antiviral Stilbene 1,2-Diamines Prevent Initiation of Hepatitis C Virus RNA Replication at the Outset of Infection(2011)18 cited
• Genotyping of hepatitis C virus in Changchun Region, China and relationship between HCV genotype and severity of liver diseases.(2009)