Redox system of Trypanosoma cruzi as possible molecular targets for sesquiterpene lactones

BARRERA P; GAIA A; SPINA R; TELLO FARAL P; ROBELLO C; CIFUENTES D; SOSA M

Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases; 2018

Instituto de la Química y Metabolismo del Fármaco

Chagas` disease is caused by Trypanosoma cruzi (T. cruzi) and affects to millions of people in Latin Americaand still spreadingout to to non- endemic areas. During its life cycle, T. cruzi should withstand extreme environmental conditions ?i.e. oxidativestress- when it passes from the insect vector to the mammalian host (Figure 1). Thereby, T. cruzi must cope with reactive oxygenspecies (ROS) produced by its own metabolism and those generated by the host immune responses. The antioxidant defensesystem of trypanosomatids differs from that of mammalian cells, since the parasites have exclusive reducing molecules andenzymes. Therefore, the parasite redox machinery could be a potential target for antiparasitic therapies. The sesquiterpenelactones (STLs) are molecules abundant in several plant families. Our study is focused on the possible oxidative action of the STLdehydroleucodine (DhL) and some derivatives DC-X1, DC-X-2, DC-X3 and DC-X4 obtained by chemical substitutions. Thesemodifications could potentiate the biological activity of DhL.. Results. As shown in the Figure 2, the molecular structure of DhL exhibits a chemical group -methylene--lactone , whichcould be reactive with thiol groups and generate an environmental oxidative. We observed an antiproliferative effect of DhL, andits derivatives on T. cruzi (strain Dm28c) (Figure 3). However, those parasites overexpressing reducing enzymes such as theperoxidises Tc-CPX and Tc-MPX, showed to be more resistant to the drug action (Figure 4). Moreover, the action of DhL wasblocked by reduced glutathione, indicating that the molecule would interfere with crucial molecules for parasite life by blockingsulphydryl groups (Figure 5). Consistent with these results, the STLs induced ROS generation on the wild type parasites (Figure 6), and , at a lesser extent, in the T. cruzi overexpressing Tc-MPX (Figure 7). All these results indicate that oxidative stress inductionis, at least, one of the mechanisms for STLs anti-parasitic action.