Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness

Hofer, Anders, Steverding, Dietmar, Chabes, Andrei, Brun, Reto and Thelander, Lars (2001) Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness. Proceedings of the National Academy of Sciences, 98 (11). pp. 6412-6416. ISSN 0027-8424

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The drugs in clinical use against African sleeping sickness are toxic, costly, or inefficient. We show that Trypanosoma brucei, which causes this disease, has very low levels of CTP, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. The CTP synthetase inhibitors 6-diazo-5-oxo-l-norleucine (DON) and alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even further and inhibited trypanosome proliferation in vitro and in T. brucei-infected mice. In mammalian cells, DON mainly inhibits de novo purine biosynthesis, a pathway lacking in trypanosomes. We could rescue DON-treated human and mouse fibroblasts by the addition of the purine base hypoxanthine to the growth medium. For treatment of sleeping sickness, we propose the use of CTP synthetase inhibitors alone or in combination with appropriate nucleosides or bases.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: EPrints Services
Date Deposited: 25 Nov 2010 11:09
Last Modified: 24 Oct 2022 03:39
DOI: 10.1073/pnas.111139498

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