Characterisation of the antitrypanosomal activity of peptidyl alpha-aminoalkyl phosphonate diphenyl esters

Two groups of irreversible serine peptidase inhibitors, peptidyl chlorometh yl ketones and peptidyl phosphonate diphenyl esters, were examined for anti trypanosomal activity against the bloodstream form of Trypanosoma brucei br ucei. Both peptidyl chloromethyl ketones and peptidyl phosphonate diphenyl eaters inhibited trypsin-like peptidases of the parasites and exhibited ant itrypanosomal activity at micromolar concentrations. In live T. b. brucei, labelled analogues of both of these groups of inhibitors primarily targeted an 80-kBa peptidase, possibly a serine oligopeptidase known as oligopeptid ase B. In an in vivo mouse model of infection, one of these inhibitors, car bobenzyloxyglycyl-4-amidinophenylglycine phosphonate diphenyl eater, was cu rative at 5 mg kg(-1) day(-1) but appeared toxic at higher doses. There was no significant correlation between the inhibitory potency las evaluated ag ainst purified T. b, brucei oligopeptidase B) and the in vitro antitrypanos omal efficacy of either group of inhibitors, suggesting that these inhibito rs were acting on multiple targets within the parasites, or had different c ell permeability properties. These findings suggest that serine peptidases may represent novel chemotherapeutic targets in African trypanosomes. (C) 2 000 Elsevier Science Inc.