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

Anders Hofer, Dietmar Steverding, Andrei Chabes, Reto Brun, Lars Thelander

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85 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)6412-6416
Number of pages5
JournalProceedings of the National Academy of Sciences
Volume98
Issue number11
DOIs
Publication statusPublished - 2001

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