Chemical evaluation of fatty acid desaturases as drug targets in Trypanosoma cruzi

ALLOATTI, ANDRÉS; TESTERO, SEBASTIÁN; UTTARO, ANTONIO D.

INTERNATIONAL JOURNAL FOR PARASITOLOGY

Elsevier

Año: 2009 vol. 39 p. 985 - 993

0020-7519

Four positional isomers of thiastearate (TS) and Isoxyl (Thiocarlide) were assayed as fatty acid desaturase inhibitors in Trypanosoma cruzi. 9-TS did not exert a significant effect on growth of T. cruzi epimastigotes, neither on the fatty acid profile of the parasite cells. 100 μM of 10-TS totally inhibited growth, with an IC50 of 3 μM. Growth inhibition was reverted by supplementing the culture media with oleate. The fatty acid profile of treated cells revealed that conversion of stearate to oleate and palmitate to palmitoleate were drastically reduced and, as a consequence, total level of unsaturated fatty acids decreased from 60 to 32%. Isoxyl, a known inhibitor of stearoyl-CoA D9 desaturase in mycobacteria, had similar effects on T. cruzi growth (IC50 2 μM) and fatty acid content, indicating that D9 desaturase was the target of both drugs. 12- and 13-TS were inhibitors of growth with IC50 values of 50 and 10 μM, respectively, but oleate or linoleate were unable to revert the effect. Both drugs increased the percentage of oleate and palmitate in the cell membrane and drastically reduced the content of linoleate from 38% to 16% and 12% respectively, which is in agreement with a specific inhibition of oleate D12 desaturase. The absence of a corresponding enzyme activity in mammalian cells and the significant structural differences between trypanosome and mammalian D9 desaturases, together with our results, highlight these enzymes as promising targets for selective chemotherapeutic intervention.