Trypanocidal effect of alpha',beta'-epoxyketones indicates that trypanosomes are particularly sensitive to inhibitors of proteasome trypsin-like activity

Glenn, Robert J., Pemberton, Alexander J., Royle, Howard J., Spackman, Robert W., Smith, Emily, Rivett, A. Jennifer and Steverding, Dietmar (2004) Trypanocidal effect of alpha',beta'-epoxyketones indicates that trypanosomes are particularly sensitive to inhibitors of proteasome trypsin-like activity. International Journal of Antimicrobial Agents, 24 (3). pp. 286-289. ISSN 1872-7913

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Abstract

Previous studies have shown that the proteasome of Trypanosoma brucei is a candidate for novel chemotherapy of African sleeping sickness. In this study, two potent and highly selective alpha',beta'-epoxyketones peptide proteasome inhibitors, epoxomicin and YU101, have been tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of T. brucei. Both inhibitors displayed promising anti-trypanosomal activities with ED(50) and ED(90) values in the low to mid nanomolar range. Based on MIC values, epoxomicin exhibited a selectivity index approaching those of commercially available drugs. Enzymatic analyses of proteasomal peptidase activities revealed that, compared with mammalian cells, trypanosomes are particular sensitive to inhibition of the trypsin-like activity of the proteasome. In conclusion, the data suggests that proteasome inhibitors targeting the trypsin-like activity are the rational choice for future 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 11:09
Last Modified: 21 Apr 2020 20:18
URI: https://ueaeprints.uea.ac.uk/id/eprint/12658
DOI: 10.1016/j.ijantimicag.2004.02.023

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