DRUG REPOSITIONING FOR THE DISCOVERY OF NEW TREATMENTS AGAINST CHAGAS DISEASE. OXIDATIVE DAMAGE REPAIR ENZYMES FROM Trypanosoma cruzi AS NEW THERAPEUTIC TARGETS

SASONI, NATALIA; GARAY, ALBERTO S.; HERRERA, FERNANDO E.; RODRIGUES, DANIEL E.; IGLESIAS, ALBERTO A.; GUERRERO, SERGIO A.; ARIAS, DIEGO G.

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Methionine is an amino acid susceptible to beoxidized to methionine sulfoxide (MetSO). The reduction of MetSO to methionineis catalyzed by methionine sulfoxide reductases (MSR), enzymes present inalmost all organisms. Recently, we characterized MSR proteins from Trypanosoma cruzi, which would be relevant for the survival ofthese pathogens in the various stages of their life cycle. Chagas is aneglected disease caused by the parasite T.cruzi, which affects underdeveloped countries. The current drugs arenifurtimox and benznidazole, but both have severe adverse effects and lesseffectivity in chronic infections; therefore, the need to discover new drugs isessential. Drug repositioning is an interesting option within theinternational drug development community. Through molecular modeling and virtual screeningusing the commercially available approved drugs extracted from ZINC database(2924), we identified drugs with potential binding capacity to T. cruzi MSR. From a preliminarymolecular docking analysis, a set of ten compounds with the best bindingenergies were selected and tested by invitro and in vivo assays. Epimastigoteand metacyclic trypomastigote cells were used to test the trypanocidal effectof ten selected compounds. Among these drugs, flunarizine, trifluoperazine,estradiol-benzoate, domperidone and itraconazole showed better or similar trypanocidaleffects (IC50 range 1 to 50 mM) in comparison with nifurtimox or benznidazole(IC50 of 6 and 20 mM, respectively). In vitro enzymatic assaysconfirmed the inhibitory effect of these drugs over methionine sulfoxidereductase activity of T. cruzi MSRs,which exhibited similar inhibitory potency. This work suggeststhat five known drugs could be used to design new therapy strategies againstChagas disease. Granted by ANPCyT (PICT2014-2103) and Fundación Bunge y Born (subsidio para investigación de la enfermedadde Chagas - 2016).