The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo

Scory, S, Stierhof, Y-D, Caffrey, CR and Steverding, D (2007) The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo. Kinetoplastid Biology and Disease, 6. ISSN 1475-9292

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Abstract

BACKGROUND: Current chemotherapy of human African trypanosomiasis or sleeping sickness relies on drugs developed decades ago, some of which show toxic side effects. One promising line of research towards the development of novel anti-trypanosomal drugs are small-molecule inhibitors of Trypanosoma brucei cysteine proteinases. RESULTS: In this study, we demonstrate that treatment of T. brucei-infected mice with the inhibitor, carbobenzoxy-phenylalanyl-alanine-diazomethyl ketone (Z-Phe-Ala-CHN2), alters parasite morphology and inhibits cell division. Following daily intra-peritoneal administration of 250 mg kg(-1) of Z-Phe-Ala-CHN2 on days three and four post infection (p.i.), stumpy-like forms with enlarged lysosomes were evident by day five p.i. In addition, trypanosomes exposed to the inhibitor had a 65% greater protein content than those from control mice. Also, in contrast to the normal 16% of parasites containing two kinetoplasts--a hallmark of active mitosis, only 4% of trypanosomes exposed to the inhibitor were actively dividing, indicating cell cycle-arrest. CONCLUSION: We suggest that inhibition of endogenous cysteine proteinases by Z-Phe-Ala-CHN2 depletes the parasite of essential nutrients necessary for DNA synthesis, which in turn, prevents progression of the cell cycle. This arrest then triggers differentiation of the long-slender into short-stumpy forms.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:
Depositing User: EPrints Services
Date Deposited: 25 Nov 2010 11:10
Last Modified: 28 Oct 2019 11:32
URI: https://ueaeprints.uea.ac.uk/id/eprint/13633
DOI: 10.1186/1475-9292-6-2

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