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Int J Antimicrob Agents. 2003 Aug;22(2):155-9.

Improved trypanocidal activities of cathepsin L inhibitors.

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Abteilung Parasitologie, Hygiene-Institut der Ruprecht-Karls-Universit├Ąt, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.


The major lysosomal cysteine proteinase of African trypanosomes is a candidate target for novel chemotherapy of sleeping sickness. This cathepsin L-like enzyme is termed rhodesain and brucipain in Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei, respectively. Three potent and selective dipeptidyl cathepsin L inhibitors have been investigated for their trypanocidal activities in vitro using culture-adapted bloodstream forms of T. b. brucei. Compared with general cysteine proteinase inhibitors used previously by ourselves and others, the present inhibitors had improved selectivity indices and, importantly, anti-trypanosomal activities comparable with those of commercial anti-sleeping sickness drugs. Using purified recombinant rhodesain, potent k(inact)/Ki values of up to 2.3x10(6) M(-1) s(-1) were recorded with the inhibitors. Also, all inhibitors blocked proteinolysis in the lysosome consistent with the inhibition of rhodesain/brucipain. In conclusion, the data support the potential of cathepsin L inhibitors for rational anti-trypanosomal drug development.

[Indexed for MEDLINE]

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