Identification of polyamine transport inhibitors: repurposing antipsychotic drugs for Chagas disease

REIGADA, CHANTAL; VALERA-VERA, EDWARD; SAYE, MELISA; MIRANDA, MARIANA; PEREIRA, CA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencia; 2019

Sociedad Argentina de Protozoología (SAP) y otras

In Trypanosoma cruzi, the etiological agent of Chagas disease, the uptake ofpolyamines constitutes a promising target to design specific inhibitors withtripanocidal effects, since it is essential for parasite survival. In a previous study,Ant4, a 9-anthracenylmethyl-putrescine conjugate, designed for cancer treatment,inhibited the polyamine transport in T. cruzi parasites and also presented a strongtrypanocidal effect on trypomastigotes, the bloodstream stage of T. cruzi.Considering the effects of Ant4 in the parasite, and that is not approved for use inhumans, in this work we proposed to identify, using in silico and in vitro strategies,trypanocidal drugs approved for the treatment of other diseases that have similarstructure and activity to Ant4. Initially, we performed a similarity ligand-basedvirtual screening in the SWEETLEAD database containing world's approved drugsand natural products, using Ant4 as reference molecule. Applying this strategy,four antipsychotic tricyclic drugs were identified to be used in experimental assaysin T. cruzi parasites. Three of them; promazine, chlorpromazine and clomipramine,showed to be effective inhibitors of polyamine uptake in epimastigotes andtrypomastigotes. The drugs also revealed a high trypanocidal activity againstamastigotes (IC50 values of 3.8, 1.9 and 2.9 μM, respectively) and trypomastigotes(IC50 values of 3.4, 2.7 and 1.3 μM, respectively) while in epimastigotes the IC50were significantly higher (34.7, 41.4 and 39.7 μM, respectively).Taking advantage of the intrinsic fluorescence signal of Ant4 and chlorpromazine,we demonstrated that both compounds are incorporated into the parasite,suggesting the existence of additional intracellular targets.In conclusion, these polyamine transport inhibitors are promising trypanocidaldrugs, in addition they are approved for use in humans, which could reducesignificantly the requirements for their possible applications in the treatment ofChagas disease.