Discovery of potent anilide inhibitors against the severe acute respiratory syndrome 3CL protease

J Med Chem. 2005 Jun 30;48(13):4469-73. doi: 10.1021/jm050184y.

Abstract

A diversified library of peptide anilides was prepared, and their inhibition activities against the SARS-CoV 3CL protease were examined by a fluorogenic tetradecapeptide substrate. The most potent inhibitor is an anilide derived from 2-chloro-4-nitroaniline, l-phenylalanine and 4-(dimethylamino)benzoic acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL protease with K(i) = 0.03 muM. The molecular docking experiment indicates that the P1 residue of this anilide inhibitor is distant from the nucleophilic SH of Cys145 in the active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / chemical synthesis*
  • Anilides / chemistry
  • Anilides / pharmacology*
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases
  • Endopeptidases / chemistry
  • Endopeptidases / drug effects
  • Endopeptidases / metabolism*
  • Kinetics
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Protein Conformation
  • Severe Acute Respiratory Syndrome / drug therapy*
  • Severe acute respiratory syndrome-related coronavirus / drug effects
  • Severe acute respiratory syndrome-related coronavirus / enzymology
  • Structure-Activity Relationship
  • Viral Proteins / chemistry
  • Viral Proteins / drug effects
  • Viral Proteins / metabolism*

Substances

  • Anilides
  • Antiviral Agents
  • Protease Inhibitors
  • Viral Proteins
  • Endopeptidases
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases