DEHYDROLEUCODINE AND SOME CHEMICAL DERIVATES AFFECT PROLIFERATION OF Trypanosoma cruzi BY ALTERING DIFFERENT MOLECULAR TARGETS.

GOMEZ J; CABALLERO P; BARRERA PA; GUARISE C; CIFUENTE DA; GAIA A; SOSA MA

Mendoza

Congreso; IV Reunión Conjunta de Sociedades de Biología de la República Argentina; 2020

Sociedad Biología de Cuyo

Chagas disease is endemic in Latin America and affects to millions of people worldwide. This pathology is caused by the trypanosomatid Trypanosoma cruzi (T. cruzi). The current chemotherapy is based on the nitroderivatives Benznidazole and Nifurtimox but their use is restricted due to the severe side effects on the patients, justifying the continuous search for alternative drugs. The antioxidant defense system of the trypanosomatids is different from that of mammalian cells, having a particular set of reducing molecules and enzymes. Hence, the redox system of the parasite emerges as an attractive target for new antiparasitic therapies. The natural sesquiterpene lactone dehydroleucodine (DhL) is known to have an important antiparasitic activity. The α-methylene group of DhL could be responsible of its biological activities, possibly by blocking the thiols groups present in reducing molecules or enzymes. In this study we attempted to elucidate the mechanism of action of DhL and eleven derivatives (named DC-X1 to DC-X11) obtained by chemical substitutions on the methylene group. We confirmed the antiproliferative effect of this natural compounds, being the most active DhL, DC-X3, DC-X6 and DC-X11. Based on the background of DhL, we focused the study on the parasite antioxidative machinery. Thereby, T. cruzi epimastigotes were incubated with DhL and DC-X6 and intracellular ROS generation was evaluated. A significant increase of ROS was induced by DhL and at lesser extent by DC-X6. This effect was blocked by adding reduced glutathione. These results suggest that DhL and DC-X6 can induce oxidative stress in the parasites by inactivation of reducing enzymes, or by capture of reducing molecules (trypanotion or glutathione), affecting their redox homeostasis. On the other hand, we observed that DC-X11 alters the cell cycle of parasites synchronized with hydroxyurea (20 mM), which could lead to the apoptosis. Through the use of chemical derivatives we confirmed the importance of the methylene group in the mechanism of action of DhL. Our study provides new insights about the possible targets for a potential drug against Chagas.