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

BARRERA P; TELLO FARAL P; SPINA RM; SOSA MA; CIFUENTE DA; GAIA A; ROBELLO C

Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018. 4th Scientific Meeting of ResNet NPND; 2018

Instituto de la Química y Metabolismo del Fármaco.Consejo Nacional de Investigaciones Científicas y Técnicas Facultad de Farmacia y Bioquímica ? Universidad de Buenos Aires

Chagas disease is caused by Trypanosoma cruzi (T. cruzi) and affects to millions of people worldwide, mostly in Latin America (1). In order to complete its life cycle, T. cruzi faces extreme environmental conditions ?i.e. oxidative stress- as it propagates from an insect vector to a mammalian host, driving the transition from non-infective: epimastigote, to infective forms: trypomastigotes (2). Thereby, T. cruzi must cope with reactive oxygen species (ROS) produced by its own metabolism and those generated by the host immune responses. The antioxidant defense system in the trypanosomatids differs from that of mammalian cells, since the parasites have exclusive reducing molecules and enzymes. Therefore, the parasite redox machinery could be a potential target for antiparasitic therapies (3, 4, 5). Natural products play a crucial role in the search for molecules with antiparasitic activities. The sesquiterpene lactones (STLs) constitute a group of molecules with diverse biological activities and they are abundant in several plant families. The molecular structure of STLs could provide redox properties and thus they could be involved in multiple oxidative biological processes (6). We have previously described to STLs as a leishmanicida drugs by oxidative stress generation (7). The present study is focused on the possible oxidative action of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives DC-X1, DC-X-2, DC-X3 and DC-X4 obtained by chemical substitutions. We observed an antiproliferative effect of DhL, and its derivatives on T. cruzi epimastigotes (strain Dm28c). However, parasites overexpressing reducing enzymes such as Tc-CPX and Tc-MPX, showed to be resistant to the drug action. Moreover, the action of DhL was blocked by reduced glutathione, indicating that the molecule would interact with sulfhydryl groups of crucial molecules for parasite life. Consistent with these results, the STLs induced ROS generation on the wild type parasites, and only at a lesser extent in the T. cruzi overexpressing Tc-CPX and Tc-MPX. All these results indicate that oxidative stress induction is, at least, one of the mechanisms for STLs antiparasitic action.