Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis

J Med Chem. 2002 Jan 31;45(3):676-84. doi: 10.1021/jm010333m.

Abstract

Targeted libraries of ketone-based cysteine protease inhibitors were synthesized and screened against cruzain, a cysteine protease implicated in Chagas' disease. A number of single digit nanomolar, low molecular weight inhibitors were identified and optimized for solubility and potency. Specifically, the best inhibitors identified have K(i) values of 0.9-10 nM and molecular weights between 499 and 609 Da. The most effective inhibitor was also found to be greater than 1000-fold selective for cruzain relative to cathepsin B and 100-fold selective for cruzain relative to cathepsin L.

Publication types

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

MeSH terms

  • Animals
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin L
  • Cathepsins / antagonists & inhibitors
  • Cysteine Endopeptidases / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Fluorometry
  • Humans
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology
  • Kinetics
  • Molecular Weight
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / chemistry
  • Solubility
  • Spectrophotometry, Ultraviolet
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Trypanosoma cruzi

Substances

  • Enzyme Inhibitors
  • Ketones
  • Protozoan Proteins
  • Sulfhydryl Compounds
  • Cathepsins
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi
  • Cathepsin B
  • CTSL protein, human
  • Cathepsin L