Methionine sulfoxide reductases from Trypanosoma cruzi as molecular targets

SASONI, N; DAVIES, C; CAMPOS, EM; GARAY, AS; BÜRGI, MDLM; ZAGO, MP; IGLESIAS, AA; GUERRERO SA; ARIAS, DG

Congreso; IX Congreso Internacional de Parasitología Neotropical, ?Ciencia e Investigación en parasitología Creando redes para la salud?; 2021

Universidad Autónoma del Carmen

Methionine is an amino acid susceptible to be oxidized to methionine sulfoxide (MetSO). The reduction of MetSO to methionine is catalyzed by methionine sulfoxide reductases (MSR), enzymes present in almost all organisms. Recently, we characterized MSR proteins from Trypanosoma cruzi, which would be relevant for the survival of these pathogens in the various stages of their life cycle. Cha-gas is a neglected disease caused by the parasite T. cruzi, which affects underde-veloped countries. The current drugs are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. Drug repositioning is an interesting option within the international drug development community. Through molecu-lar modeling and virtual screening using the commercially available approved drugs extracted from the ZINC database (2924), we identified drugs with the potential binding capacity to T. cruzi MSR. From a preliminary molecular dock-ing analysis, a set of ten compounds with the best binding energies were selected and tested by in vitro and in vivo assays. Epimastigote and metacyclic trypo-mastigote cells were used to test the trypanocidal effect. Among these drugs, flunarizine, trifluoperazine, estradiol-benzoate, domperidone, and itraconazole showed better or similar trypanocidal effects in comparison with nifurtimox or benznidazole. In vitro enzymatic and thermal shift assays confirmed the inhibitory effect of these drugs over activity of T. cruzi MSRs, which exhibited similar inhibitory potency. This work suggests that known drugs could be used to de-sign new therapy strategies against Chagas disease. Granted by ANPCyT (PICT2016-1778 and PICT2017-2268) and Fundación Bunge y Born.