Drug repositioning in trypanosomatid parasites using the proline transporter TcAAAP069 as molecular target

SAYÉ, MELISA; REIGADA, CHANTAL; DIDWANIA, NICKY; VALERA-VERA, EDWARD; MIRANDA, MARIANA R; ALI, NAHID; PEREIRA, CLAUDIO A

Conferencia; NTD Network Early Career Researcher Conference 2021; 2021

Trypanosoma cruzi, the etiological agent of Chagas disease, has ametabolism largely based on the consumption of glucose andproline. Proline is also involved in differentiation processes, cellularinvasion and resistance to different stresses. Up to date, thepermease TcAAAP069 is the only proline transporter identified in T.cruzi and we have reported its importance on parasite survival.Interestingly, the AAAP family is present in all trypanosomatidparasites and their members are significantly different from thehuman transporters. Using an in silico approach we identified newTcAAAP069 inhibitors with trypanocidal activity from a database ofdrugs already approved to use in humans. Cyproheptadine andloratadine, both antihistamines, and the antibiotic clofazimine,were able to inhibit proline transport and presented a similar oreven better activity than benznidazole, the drug currently used totreat Chagas disease, against epimastigotes, trypomastigotes andamastigotes of T. cruzi. In addition, a synergistic effect wasobserved between benznidazole and a combination of the threedrugs. We also evaluated the in vitro antiprotozoal effect of thesedrugs in the trypanosomatids T. brucei and L. donovani. Theantiprotozoal activity was similar to the obtained in T. cruzi. Sinceproline permease TcAAAP069 has orthologous genes in Leishmaniaand T. brucei, LdAAP24 and TbAAT6, these compounds will beevaluated as inhibitors of the proline transport on both parasites aspossible mechanism of action of such drugs.The strategy herein applied, based on the screening of approvedcompounds used to treat other pathologies, is known as drugrepositioning. One of its main advantages is that reduces the timeand the economic cost of implementation of new therapeuticalternatives, which is especially important in neglected diseases.