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