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

^*Medical Biochemistry, Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden; ^‡Department of Parasitology, University of Heidelberg, Im Neuenheimer Feld 324, D-69120, Germany; and ^§Parasite Chemotherapy, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland

Communicated by Peter A. Reichard, Karolinska Institute, Stockholm, Sweden (received for review February 15, 2001)

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 α-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.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: andhof{at}panther.cmb.umu.se.
↵ ¶ The combination of glutamine analog CTP synthetase inhibitors together with nucleobases and nucleosides against parasitic protozoa is covered by a Swedish patent application filed under the number SE 0001531-3.
Abbreviations:

DON,

6-diazo-5-oxo-l-norleucine;

acivicin,

α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid