title: 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.affiliation: Department of Chemistry, University of California, Berkeley, California 94720, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Huang
authors.forename: Alice
authors.initials: A
authors.lastname: Lee
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005470:Fluorometry; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008970:Molecular Weight; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D014349:Trypanosoma cruzi
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D015800:Protozoan Proteins; D013438:Sulfhydryl Compounds; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L