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

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.

• Authors: Lily Huang, Alice Lee, Jonathan A Ellman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 3 Pg. 676-84 (Jan 31 2002) ISSN: 0022-2623 [Print] United States
• PMID: 11806719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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