Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness.
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.
Hofer
A
A
Medical Biochemistry, Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden. andhof@panther.cmb.umu.se
Steverding
D
D
Chabes
A
A
Brun
R
R
Thelander
L
L
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003562:Cytidine / Q000494:pharmacology; D003570:Cytidine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D003980:Diazooxonorleucine / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000166:cytology; D006147:Guanine / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007042:Hypoxanthines / Q000494:pharmacology; D007424:Intracellular Fluid; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D014544:Uridine Triphosphate / Q000378:metabolism
D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D007555:Isoxazoles; D014344:Trypanocidal Agents; D003980:Diazooxonorleucine; D003562:Cytidine; D006147:Guanine; D003570:Cytidine Triphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; C006303:acivicin; D014544:Uridine Triphosphate