Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter

SAYÉ, MELISA; FARGNOLI, LUCÍA; REIGADA, CHANTAL; LABADIE, GUILLERMO R.; PEREIRA, CLAUDIO A.

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

ELSEVIER SCIENCE BV

Año: 2017

0304-4165

Background. Trypanosoma cruzi, the etiological agent of Chagas disease, usesproline as its main carbon source, essential for parasite growth and stagedifferentiation in epimastigotes and amastigotes. Since proline is involved in manyessential biological processes in T. cruzi, its transport and metabolism areinteresting drug targets.Methods. Four synthetic proline analogues (ITP-1B/1C/1D/1G) were evaluated asinhibitors of proline transport mediated through the T. cruzi proline permeaseTcAAAP069. The trypanocidal activity of the compounds was also assessed.Results. The compounds ITP-1B and ITP-1G inhibited proline transport mediatedthrough TcAAAP069 permease in a dose-dependent manner. The analogues ITP-1B, -1D and -1G had trypanocidal effect on T. cruzi epimastigotes with IC50 valuesbetween 30 to 40 μM. However, only ITP-1G trypanocidal activity was related withits inhibitory effect on TcAAAP069 proline transporter. Furthermore, this analoguestrongly inhibited the parasite stage differentiation from epimastigote to metacyclictrypomastigote. Finally, compounds ITP-1B and ITP-1G were also able to inhibitthe transport mediated by other permeases from the same amino acid permeasesfamily, TcAAAP.Conclusions. It is possible to design synthetic amino acid analogues withtrypanocidal activity. The compound ITP-1G is an interesting starting point for newtrypanocidal drug design which is also an inhibitor of transport of amino acids andpolyamines mediated by permeases from the TcAAAP family, such as prolinetransporter TcAAAP069 among others.