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

MARTÍNEZ SAYÉ M; REIGADA C; DIDWANIA N; VALERA VERA E; MIRANDA MR; ALI N; PEREIRA CA

Conferencia; NTD Network Early Career Researcher Conference 2021; 2021

Global Challenges Research Fund

Trypanosoma cruzi, the etiological agent of Chagas disease, has a metabolism largely based on the consumption of glucose and proline. Proline is also involved in differentiation processes, cellular invasion and resistance to different stresses. Up to date, the permease 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 trypanosomatid parasites and their members are significantly different from the human transporters. Using an in silico approach we identified new TcAAAP069 inhibitors with trypanocidal activity from a database of drugs already approved to use in humans. Cyproheptadine and loratadine, both antihistamines, and the antibiotic clofazimine, were able to inhibit proline transport and presented a similar or even better activity than benznidazole, the drug currently used to treat Chagas disease, against epimastigotes, trypomastigotes and amastigotes of T. cruzi. In addition, a synergistic effect was observed between benznidazole and a combination of the three drugs. We also evaluated the in vitro antiprotozoal effect of these drugs in the trypanosomatids T. brucei and L. donovani. The antiprotozoal activity was similar to the obtained in T. cruzi. Since proline permease TcAAAP069 has orthologous genes in Leishmania and T. brucei, LdAAP24 and TbAAT6, these compounds will be evaluated as inhibitors of the proline transport on both parasites as possible mechanism of action of such drugs.The strategy herein applied, based on the screening of approved compounds used to treat other pathologies, is known as drug repositioning. One of its main advantages is that reduces the time and the economic cost of implementation of new therapeutic alternatives, which is especially important in neglected diseases.