Evaluation of novel inhibitors of fatty acid desaturases for chemotherapy of trypanosomatids

ALLOATTI, ANDRÉS; TRIPODI, KARINA; UTTARO, A. D.

Mar del Plata

Congreso; IX Congreso Argentino de Protozoología y Enfermedades Parasitarias; 2011

Sociedad Argentina de Protozoología

Trypanosomatids are the etiological agents of several diseases in developing countries (such as Chagas’ disease or sleeping sickness). There are no vaccines available to prevent these serious infections. In addition, few drugs are available, but those currently used are often toxic and sometimes ineffective as parasites can generate drug resistance. Therefore, there is an urgent need for the identification of new promising targets, as well as the development of new drugs, affordable, more efficacious and safe. We have previously demonstrated that genetic and chemical interference of D9 and D12 desaturases (mainly involved in maintaining the membrane fluidity in physiological conditions –by means of 18:1 and 18:2 synthesis–) seriously compromised the parasites’ survival. A few desaturase inhibitors were tested, e.g. thiastearic acids and Isoxyl (a compound used to treat tuberculosis in the 60s). Herein, we show additional results that highlight the previous chemical approach in different ways. First, we tested novel D9 and D12 desaturase inhibitors on T. brucei, T. cruzi and L. major cultures at different stages. Second, we performed synergy assays using inhibitors of both desaturases at the same time. As a result, a drastic decrease in EC50 (the concentration of drug required to cause 50% inhibition of the growth rate) was demonstrated if compared with each inhibitor EC50 value separately. Indeed, for T. brucei bloodstream form and T. cruzi epimastigotes, some pair of inhibitors showed EC50 values ranging between 1 and 10 nM. Leishmania major was considerably less susceptible to all of the compounds than the other trypanosomatids, probably as a consequence of the differences in their poly-unsaturated fatty acids biosynthetic pathway.