Peptidomimetic escape mechanisms arise via genetic diversity in the ligand-binding site of the hepatitis C virus NS3/4A serine protease.

ABSTRACT:

Background & aims

It is a challenge to develop direct-acting antiviral agents that target the nonstructural protein 3/4A protease of hepatitis C virus because resistant variants develop. Ketoamide compounds, designed to mimic the natural protease substrate, have been developed as inhibitors. However, clinical trials have revealed rapid selection of resistant mutants, most of which are considered to be pre-existing variants.

Methods

We identified residues near the ketoamide-binding site in x-ray structures of the genotype 1a protease, co-crystallized with boceprevir or a telaprevir-like ligand, and then identified variants at these positions in 219 genotype-1 sequences from a public database. We used side-chain modeling to assess the potential effects of these variants on the

SUBMITTER: Welsch C 

PROVIDER: S-EPMC3288278 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature