Quinolones as HCV NS5B polymerase inhibitors

Bioorg Med Chem Lett. 2011 Jan 1;21(1):82-7. doi: 10.1016/j.bmcl.2010.11.068. Epub 2010 Nov 21.

Abstract

Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.

MeSH terms

  • Allosteric Regulation
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / enzymology*
  • Quinolones / chemical synthesis
  • Quinolones / chemistry*
  • Quinolones / pharmacology
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Quinolones
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus