Chemical Validation of Trypanosoma brucei Fatty Acid Desaturases as Drug Targets

ALLOATTI, ANDRÉS; ROJAS, FEDERICO; UTTARO, ANTONIO D.

Villa Carlos Paz, Cordoba, Argentina

Congreso; SAIB 44th Annual Meeting; 2008

Sociedad Argentina de Investigaciones Bioquímicas y Biología Molecular

Trypanosomatids are causative agents of several diseases in developmental countries. The drugs used to treat the parasites have important disadvantages such as severe side effects, strain resistance, and variable efficacy. So, the development of more secure and efficient drugs is needed. Thiastearic acids (TS) showed toxic effect on C. fasciculata and Leishmania spp. while Isoxyl was used previously to treat tuberculosis. Both compounds seem to inhibit unsaturated fatty acid (UFA) synthesis. In this work, we propose that UFA synthesis is essential for parasites, and inhibitors of this pathway could affect trypanosomes growth. Therefore, we treated cultures of Trypanosoma brucei, bloodstream (BSF) and procyclic (PCF) forms with 4 positional isomers of TS and Isoxyl.In PCF, 9-TS (TS with sulfur at position 9) showed poor growth inhibition while 10-, 12-, 13-TS and Isoxyl showed a concentration dependant growth inhibition. 10-TS effect was reverted by oleate, indicating that its target was the D9 desaturase. 12- and 13-TS were synthesized as putative inhibitors of D12 desaturase, which was confirmed by analyzing the fatty acid profile of treated and untreated cells.BSF showed a slightly different behavior, but parasite growth was inhibited when drug concentration reached a minimum inhibitory concentration with all compounds, validating both desaturases as promissory drug targets.