Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect

Nature. 2010 May 6;465(7294):96-100. doi: 10.1038/nature08960. Epub 2010 Apr 21.

Abstract

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antiviral Agents / blood
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cell Line
  • Chlorocebus aethiops
  • Drug Resistance, Viral
  • Female
  • Genotype
  • HeLa Cells
  • Hepacivirus / drug effects*
  • Hepatitis C / drug therapy
  • Hepatitis C / virology
  • Humans
  • Imidazoles / blood
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Male
  • Middle Aged
  • Time Factors
  • Vero Cells
  • Viral Load / drug effects
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Young Adult

Substances

  • Antiviral Agents
  • Imidazoles
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • daclatasvir