Improved trypanocidal activities of cathepsin L inhibitors

Nkemgu, NJ, Grande, R, Hansell, E, McKerrow, JH, Caffrey, CR and Steverding, D (2003) Improved trypanocidal activities of cathepsin L inhibitors. International Journal of Antimicrobial Agents, 22 (2). pp. 155-159. ISSN 1872-7913

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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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: EPrints Services
Date Deposited: 25 Nov 2010 11:10
Last Modified: 21 Mar 2019 10:55

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