Transporters of amino acids and derivatives from Trypanosoma cruzi as potential therapeutic targets.

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

CABA

Jornada; XVIII Jornadas Anuales Multidisciplinarias Sociedad Argentina de Biología (SAB); 2016

Sociedad Argentina de Biología (SAB)

T. cruzi has a metabolism largely based on amino acid consumption, mainly proline, which constitutesthe main carbon and energy source in the insect stage of the parasite life cycle. In addition, proline participates in the progression of life cycle in the host cells, and it is also involved in oxidative stress and trypanocidal drugs resistance. Polyamines are essential molecules for all living organisms. T. cruzi is unable to synthetize de novo these molecules, so its acquisition relies exclusively in transport mechanisms. Nowadays there are only two drugs approved for treatment of Chagas disease with limited efficacy and severe side effects. Since amino acids and polyamines participate in a variety of metabolic routes leading to many crucial compounds for survival of T. cruzi, transporters and enzymes related totheir metabolism become interesting targets. In this work we evaluated gentian violet (GV) and isotretinoin as trypanocidal drugs targeting transporters from the T. cruzi Amino Acid/Auxin Permeases (TcAAAP) family. GV was used for several years as a blood additive for prevention of transfusion transmitted Chagas disease and it was reported that inhibition of protein synthesis by GV could be due to inhibition of amino acid uptake. Our results showed that GV enters at least in part through the proline permease TcAAAP069. On the other hand, using a combined in silico strategy for drug repositioning, isotretinoin, a safe drug used for acne treatment, was selected for in vitro studies. Our results indicate that isotretinoin acts as a trypanocidal drug through the TcAAAP transporter family. Taken together, theresults suggest that this permeases family constitutes an interesting target for drug development.