Improved trypanocidal activities of cathepsin L inhibitors

Njinkeng Joseph Nkemgu, Rachel Grande, Elizabeth Hansell, James H. McKerrow, Conor R. Caffrey, Dietmar Steverding

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28 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)155-159
Number of pages5
JournalInternational Journal of Antimicrobial Agents
Volume22
Issue number2
DOIs
Publication statusPublished - 2003

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