Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2165-2170. doi: 10.1016/j.bmcl.2018.05.012. Epub 2018 May 8.

Abstract

A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.

Keywords: Antiviral; Norovirus; Peptide; Protease inhibitor.

Publication types

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

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Norovirus / drug effects*
  • Norovirus / enzymology
  • Peptide Hydrolases / metabolism*
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Peptidomimetics
  • Protease Inhibitors
  • Peptide Hydrolases