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Two groups of irreversible serine peptidase inhibitors, peptidyl chloromethyl ketones and peptidyl phosphonate diphenyl esters, were examined for antitrypanosomal activity against the bloodstream form of Trypanosoma brucei brucei. Both peptidyl chloromethyl ketones and peptidyl phosphonate diphenyl esters inhibited trypsin-like peptidases of the parasites and exhibited antitrypanosomal activity at micromolar concentrations. In live T. b. brucei, labelled analogues of both of these groups of inhibitors primarily targeted an 80-kDa peptidase, possibly a serine oligopeptidase known as oligopeptidase B. In an in vivo mouse model of infection, one of these inhibitors, carbobenzyloxyglycyl-4-amidinophenylglycine phosphonate diphenyl ester, was curative at 5 mg kg(-1) day(-1) but appeared toxic at higher doses. There was no significant correlation between the inhibitory potency (as evaluated against purified T. b. brucei oligopeptidase B) and the in vitro antitrypanosomal efficacy of either group of inhibitors, suggesting that these inhibitors were acting on multiple targets within the parasites, or had different cell permeability properties. These findings suggest that serine peptidases may represent novel chemotherapeutic targets in African trypanosomes.

Original publication

DOI

10.1016/s0006-2952(00)00459-7

Type

Journal article

Journal

Biochemical pharmacology

Publication Date

11/2000

Volume

60

Pages

1497 - 1504

Addresses

School of Molecular and Cellular Biosciences: Biochemistry, University of Natal, Scottsville, South Africa.

Keywords

Animals, Mice, Inbred BALB C, Mice, Trypanosoma brucei brucei, Trypanosomiasis, African, Disease Models, Animal, Disease Progression, Esters, Alkanes, Peptide Hydrolases, Protease Inhibitors, Trypanocidal Agents, Binding Sites, Kinetics