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

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.
Authors	A Hofer, D Steverding, A Chabes, R Brun, L Thelander
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 11 Pg. 6412-6 (May 22 2001) ISSN: 0027-8424 [Print] United States
PMID	11353848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Enzyme Inhibitors Hypoxanthines Isoxazoles Trypanocidal Agents Diazooxonorleucine Cytidine Guanine Cytidine Triphosphate Guanosine Triphosphate Adenosine Triphosphate Carbon-Nitrogen Ligases CTP synthetase acivicin Uridine Triphosphate
Topics	Adenosine Triphosphate (metabolism) Animals Carbon-Nitrogen Ligases (antagonists & inhibitors) Cells, Cultured Cytidine (pharmacology) Cytidine Triphosphate (biosynthesis, metabolism) Diazooxonorleucine (pharmacology, therapeutic use) Enzyme Inhibitors (pharmacology, therapeutic use) Fibroblasts (cytology) Guanine (pharmacology) Guanosine Triphosphate (metabolism) Humans Hypoxanthines (pharmacology) Intracellular Fluid Isoxazoles (pharmacology, therapeutic use) Mice Mice, Inbred BALB C Trypanocidal Agents (pharmacology, therapeutic use) Trypanosoma brucei brucei (drug effects, enzymology, growth & development) Trypanosomiasis, African (blood, drug therapy, parasitology) Uridine Triphosphate (metabolism)

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