ISOTRETINOIN INHIBITS ESSENTIAL METABOLITES TRANSPORT AND EXERTS TRYPANOCIDAL ACTIVITY

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

Córdoba

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

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Trypanosoma cruzi is the etiological agent of Chagas disease, a major health problem in Latin America. Polyamines are polycationiccompounds that play a critical role in regulation of cell growth and differentiation. In the specific case of T. cruzi, which is auxotrophfor polyamines, the transport systems are the only way to obtain such molecules. Previous works reported that retinol acetate inhibitsLeishmania growth and decreases its intracellular polyamine concentration. This work describes a combined strategy of drugrepositioning 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 dockingtechniques isotretinoin, a well-known and safe drug used for acne treatment, bound to substrate recognition residues of TcPAT12 andwas chosen for further in vitro studies. Isotretionoin inhibited the polyamine transport, and also all tested amino acid transporters fromthe same protein family (TcAAAP), with calculated IC50 values in the range of 4.6?10.3 µM. In addition, this drug showed a hightrypanocidal effect on trypomastigotes, with an IC50 in the nanomolar range. These results suggest that isotretinoin is a promisingtrypanocidal drug, being a multitarget inhibitor of essential metabolites transporters.