Characterization of the Disulfiram effect in Trypanosoma cruzi

Abstract

This proposal aims to elucidate the mechanism(s) involved in the trypanocidal effect exhibited by the tetraethylthiuram disulfide drug, - commercially known as Disulfiram ® (herein named as DSF), on the parasite causing of Chagas's disease, the Trypanosoma cruzi. The DSF is susceptible to metabolic breakdown, and therefore their metabolic derivatives will be also analysed; so it will be named as DSF-effect. The inhibitory effect of DSF on both proliferative and infective forms of T. cruzi had been already observed by our group, thus provided some results that we consider as relevant to further approach. In addition, we have seen that DSF impairs the specific activity on the mitochondrial enzyme delta-1-pyrroline-5-carboxylate dehydrogenase; the second enzyme of proline's breakdown pathway. This fact suggests that, the proline metabolism impairment leads in parasite growth diminution through mechanisms not well established so far. Considering the intraspecific variability presented in T. cruzi, we will address to evaluate the DSF-effect on both proliferative and infective forms coming from distinct strains of T. cruzi. The DSF-effect will also be evaluated in the experimental infection in mice. Once it has been completed, we will characterize the type of cell death thereby involved. Our previous data suggest that DSF is active within parasite's mitochondrion, and thus some mitochondrial functions, upon DSF-effect, will be also evaluated. In parallel, aiming to unveil the pathways and/or metabolic targets involved in the DSF-effect, we also intend to perform a metabolomic analysis. These data in together will provide relevant information regarding the alternative use of FDA-approved drugs, and thus might validate mitochondrial metabolic pathways as prompt targets for efficient drug design against Chagas disease. ENUNCIADO DO PROBLEMA (AU)