IHEM   20887
Unidad Ejecutora - UE
congresos y reuniones científicas
Novel repositioned drugs for the treatment of Chagas disease.
San Pablo
Simposio; V Symposium on Drug Design and Development for Neglected Diseases; 2018
Institución organizadora:
Faculty of Pharmaceutical Sciences. University of Sao Paulo.
Chagas disease (CD) caused by the protozoan parasite Trypanosoma cruzi, is one of the most widespread neglected tropical disease in the world. In addition to the sanitary problem and economic burden produced in endemic countries, CD is currently expanded to non-endemic countries owing to migration currents. The approved drugs for CD, Benznidazole (BNZ) and, in the second line, Nifurtimox, display high toxicity and low effectiveness especially in the chronic symptomatic stage. Last years, public and private organizations generate collaborative projects to develop more effective and safe treatments for Chagas. In this context, drug repositioning arises as one of the most successful strategies to find new therapies as a result of its rapid and low cost effective drug development. In our laboratory, in collaboration with other groups, we tested the biological action of different compounds directed against the main T. cruzi targets under different experimental approaches. Currently we are evaluating the trypanocidal effect of two repositioned drugs. Carvedilol (Carve) is a non-selective beta-blocker initially selected by a virtual screening of compounds with structures similar to K777, an effective cruzipain (Cz) inhibitor but hepatotoxic. Although Carve did not inhibit the Cz activity in vitro, we observed a significant effect of Carve on T. cruzi morphology and parasite replication. The other compound, difluoromethylornithine (DFMO), currently used for the treatment of the Human African Trypanosomiasis, is an inhibitor of ornithine decarboxylase (ODC), an enzyme required for the polyamine (PA) biosynthesis. Although DFMO was discarded for CD treatment because of the absent of the ODC gene in T. cruzi, we propose its use in combination with BNZ as an enhancer of the parasite susceptibility to BNZ. Interestingly data show a significant trypanocidal effect of the combination BNZ/DFMO, resulting in a reduction of the IC50 for BNZ of at list two folds compared with BNZ monotherapy. Ongoing experiments using in vivo models of infection will confirm us the beneficious action of this combined therapy. Until now, the increase in the anti-parasitic efficacy together with the possible reduction of host toxicity make the combination BNZ/DFMO a good candidate to progress to clinical studies.