Drug repositioning for the discovery of new treatments against Chagas disease. Oxidative damage repair enzymes from Trypanosoma cruzi as new therapeutic targest

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

Buenos Aires

Congreso; Reunión conjunta de Sociedades de Biociencias, XLVI Reunión anual de la Sociedad Argentina de Biofísica (SAB); 2017

Sociedad Argentina de Biofísica

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. Chagas is a neglected disease caused by the parasite T. cruzi, which affects underdeveloped 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 molecular modeling and virtual screening using the commercially available approved drugs extracted from ZINC database (2924), we identified drugs with potential binding capacity to T. cruzi MSR. From a preliminary molecular docking 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 trypomastigote cells were used to test the trypanocidal effect of ten selected compounds. Among thesedrugs, flunarizine, trifluoperazine, estradiol-benzoate, domperidone and itraconazole showed better or similar trypanocidal effects (IC 50 range 1 to 50 mM) in comparison with nifurtimox or benznidazole (IC 50 of 6 and 20 mM, respectively). In vitro enzymatic assays confirmed the inhibitory effect of these drugs over methionine sulfoxide reductase activity of T. cruzi MSRs, which exhibited similar inhibitory potency. This work suggests that five known drugs could be used to design new therapy strategies against Chagas disease.