Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6317-20. doi: 10.1016/j.bmcl.2013.09.070. Epub 2013 Sep 30.


A class of tripeptidyl transition state inhibitors containing a P1 glutamine surrogate, a P2 leucine, and a P3 arylalanines, was found to potently inhibit Norwalk virus replication in enzyme and cell based assays. An array of warheads, including aldehyde, α-ketoamide, bisulfite adduct, and α-hydroxyphosphonate transition state mimic, was also investigated. Tripeptidyls 2 and 6 possess antiviral activities against noroviruses, human rhinovirus, severe acute respiratory syndrome coronavirus, and coronavirus 229E, suggesting a broad range of antiviral activities.

Keywords: Coronavirus 229E; Human rhinovirus; Norovirus; Severe acute respiratory syndrome coronavirus; Viral 3C and 3C-like protease inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism*
  • Drug Design
  • Glutamine / analogs & derivatives
  • Glutamine / pharmacology
  • Humans
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Antiviral Agents
  • Protease Inhibitors
  • Glutamine
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases