ISOTRETINOIN INHIBITS ESSENTIAL METABOLITES TRANSPORT AND EXERTS TRYPANOCIDAL ACTIVITY

REIGADA C; VALERA VERA EA; SAYE M; MIRANDA MR; PEREIRA CA

Congreso; LII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2016

Trypanosomacruzi is the etiological agent of Chagas disease, a major health problem in Latin America. Polyamines are polycationic compounds that play a critical role in regulation of cell growth and differentiation. In the specific case of T. cruzi, which is auxotroph for polyamines, the transport systems are the only way to obtain such molecules. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. This work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit the only polyamines transporter, TcPAT12. Seven retinoids used in medicine were obtained by similarity screening of 3,000 FDA approved drugs. Using molecular docking techniques isotretinoin, a well-known and safe drug used for acne treatment, bound to substrate recognition residues of TcPAT12 and was chosen for further in vitro studies. Isotretionoin inhibited the polyamine transport, and also all tested amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6?10.3 µM. In addition, this drug showed a high trypanocidal effect on trypomastigotes, with an IC50 in the nanomolar range. These results suggest that isotretinoin is a promising trypanocidal drug, being a multitarget inhibitor of essential metabolites transporters