title: Characterisation of the antitrypanosomal activity of peptidyl alpha-aminoalkyl phosphonate diphenyl esters.
abstract: 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.
authors.affiliation: School of Molecular and Cellular Biosciences: Biochemistry, University of Natal, Scottsville, South Africa.
authors.forename: R E
authors.initials: RE
authors.lastname: Morty
authors.forename: L
authors.initials: L
authors.lastname: Troeberg
authors.forename: J C
authors.initials: JC
authors.lastname: Powers
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: J D
authors.initials: JD
authors.lastname: Lonsdale-Eccles
authors.forename: T H
authors.initials: TH
authors.lastname: Coetzer
mesh_terms: D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D018450:Disease Progression; D004952:Esters / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000201:enzymology
chemical_list: D000473:Alkanes; D004952:Esters; D011480:Protease Inhibitors; D014344:Trypanocidal Agents; D010447:Peptide Hydrolases; C028759:oligopeptidase