Trypanosoma brucei: β2-selective proteasome inhibitors do not block the proteasomal trypsin-like activity but are trypanocidal

Steverding, Dietmar, Florea, Bogdan I. and Overkleeft, Herman S. (2019) Trypanosoma brucei: β2-selective proteasome inhibitors do not block the proteasomal trypsin-like activity but are trypanocidal. Molecular and Biochemical Parasitology, 227. pp. 1-4. ISSN 0166-6851

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    Previous studies indicated that the proteasome of the protozoan parasite Trypanosoma brucei is particularly sensitive to inhibition of the trypsin-like activity. In this study, three newly developed β2 subunit-specific inhibitor (LU-102, LU-002c and LU-002i) were tested for their ability to block the trypsin-like activity of the trypanosomal proteasome. At 10 µM, none of the compounds affected the proteasomal trypsin-like activity in cell lysates of bloodstream forms of T. brucei. On the other hand, leupeptin, a well-established β2 inhibitor, supressed the proteasomal trypsin-like activity within trypanosome cell lysates with a 50% inhibitory concentration of 2 µM demonstrating the inhibitability of the trypsin-like activity of the T. brucei proteasome under the experimental condition. Nevertheless, two compounds (LU-102 and LU-002i) displayed moderate trypanocidal activity with 50% growth inhibition values of 6.9 and 8.5 µM, respectively. In the case of LU-102, it was shown that the trypanocidal activity of the compound was due to inhibition of the major lysosomal cysteine protease TbCATL. The main finding of this study indicate substantial inhibitor sensitivity differences between the trypsin-like sites of the human and trypanosomal proteasomes. Whether these differences can be exploited for the design of anti-trypanosomal drug therapies remains to be shown.

    Item Type: Article
    Uncontrolled Keywords: trypanosoma brucei,african trypanosomiasis,proteasome,β2 subunit-specific inhibitors
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    Depositing User: LivePure Connector
    Date Deposited: 12 Nov 2018 15:30
    Last Modified: 20 Jun 2019 11:43
    DOI: 10.1016/j.molbiopara.2018.11.002

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