TARGETING PROLINE TRANSPORT FOR CHAGAS´ DISEASE DRUG DEVELOPMENT

FARGNOLI, L; PAGURA, L; CRICCO, J; SILBER, A.M.

Campinas

Workshop; Sao Paulo School of Advanced Science on Neglected Diseases Drug Discovery focus on Kinetoplastids (SPSAS-ND3); 2015

Brazilian Biosciences National Laboratory (LNBio) at the Brazilian Center for Research in Energy and Materials (CNPEM)

L-Proline (L-Pro)is an important amino acid for protozoan parasite of the genusTrypanosoma and Leishmania, which include the causative agents of Chagas´s disease, African sleeping sickness and leishmaniasis. In Trypanosoma cruzi, the etiological agent of Chagas´ disease, this amino acid is involved in energy metabolism, differentiation processes and resistance to osmotic stress. In thisstudy, we pretended to explore the scope of L-Pro uptake as a chemotherapeutic target for T. cruzi. The designed inhibitors contained L-Pro as recognizable motif, a linker and a variable region to be able to block the transporter. The final products were a series of 1,2,3-triazolyl-proline derivatives prepared starting from L-Pro through alkylation and copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry) and were tested against T. cruzi epimastigotes. L-Pro uptake inhibition of the most active compounds was assayed to validate the mechanism of action showing a decrease in the aminoacid uptake. The analogues antiparasitic activity seems to be related to long aliphatic chains substitution over the triazole. In order to determine the therapeutic index of the hits found the cytotoxicity on Vero cells is being evaluated. In addition, a series of fluorescent tagged analogs are being prepared to study the internalization and location within the parasite by fluorescent microscopy.