Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors

Bioorg Med Chem Lett. 2013 Jan 1;23(1):62-5. doi: 10.1016/j.bmcl.2012.11.026. Epub 2012 Nov 21.

Abstract

Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED(50) of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / metabolism
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Norovirus / enzymology*
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / metabolism
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Sulfites / chemical synthesis
  • Sulfites / chemistry*
  • Sulfites / metabolism
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Antiviral Agents
  • Protease Inhibitors
  • Sulfites
  • Viral Proteins
  • Peptide Hydrolases
  • hydrogen sulfite