Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase

Affordable Access

Publisher Website

Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase

Authors
Publisher
Public Library of Science
Volume
7
Issue
7
Identifiers
DOI: 10.1371/journal.pone.0040029
Keywords
  • Computer Science
  • Biology
  • Biochemistry
  • Medicine
  • Infectious Diseases
  • Proteins
  • Drug Discovery
  • Hepatitis
  • Computer Modeling
  • Research Article
  • Hepatitis C
  • Viral Diseases
  • Computer-Aided Design
  • Chemical Biology
  • Computer Applications
  • Small Molecules
  • Protein Interactions
  • Biomacromolecule-Ligand Interactions

Abstract

Background Hepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors. Methodology/Principal Findings To circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified. Conclusions/Significance Overall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals.

There are no comments yet on this publication. Be the first to share your thoughts.