Trypanocidal activity of polyamines transport inhibitors.

REIGADA, CHANTAL; PEREIRA, CA; PHANSTIEL, OTTO; MIRANDA, MARIANA

CABA

Congreso; XXIX Reunión Anual de la Sociedad Argentina de Protozoología (SAP); 2017

Sociedad Argentina de Protozoología (SAP)

Polyamines play a critical role as regulators of cell growth and differentiation.In contrast with other protozoa, Trypanosoma cruzi isauxotrophic for polyamines; therefore, their intracellular availabilitydepends exclusively on transport processes. Thus, the inhibition ofthese processes can alter the viability of the parasite. The polyamineanalogues used in this work were successfully tested in cancercells, bacteria, fungi and also showed a potent antiplasmodial effect,inhibiting polyamine transport. We evaluated the activity of thesecompounds on polyamine transport in T. cruzi and we assessedits effects on parasite viability. Three polyamine derivatives, AMXT1501, Ant4 and Ant44, inhibited the putrescine transport in epimastigotes(the insect stage of T. cruzi) with calculated IC50 values of3.29, 5.01 and 3.98 μM, respectively. The Ant4 analogue showeda trypanocidal effect on trypomastigotes (the bloodstream stage ofT. cruzi) with an IC50 of 462 nM, while in epimastigotes the IC50 wassignificantly higher (16.97 μM). In addition, we studied the effect ofthe combination of benznidazole, a drug used in treating Chagasdisease, with Ant4 on the viability of epimastigotes. The combinedtreatment produced a significant increase on the inhibition of parasitesgrowth compared with individual treatments. In summary, theseresults suggest that Ant4, a putrescine conjugate, is a promisingdrug for the treatment of Chagas disease because it showed a potenttrypanocidal effect by inhibiting polyamines transport.