Trypanocidal effect of isotretinoin through the inhibition of polyamine and amino acid transporters in Trypanosoma cruzi

REIGADA C; VALERA VERA EA; SAYÉ M; ERRASTI AE; AVILA CC; MIRANDA MR; PEREIRA CA

PLOS NEGLECTED TROPICAL DISEASES

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2017

1935-2735

Polyamines are essential compounds to all living organisms and in the specific case of Trypanosomacruzi, the causative agent of Chagas disease, they are exclusively obtainedthrough transport processes since this parasite is auxotrophic for polyamines. Previousworks reported that retinol acetate inhibits Leishmania growth and decreases its intracellularpolyamine concentration. The present work describes a combined strategy of drug repositioningby virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12,the only polyamine transporter described in T. cruzi. After a screening of 3000 FDAapproveddrugs, 7 retinoids with medical use were retrieved and used for molecular dockingassays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used foracne treatment, showed the best interaction score with TcPAT12 and was selected for furtherin vitro studies. Isotretinoin inhibited the polyamine transport, as well as other aminoacid transporters from the same protein family (TcAAAP), with calculated IC50 values inthe range of 4.6±10.3 μM. It also showed a strong inhibition of trypomastigote burst frominfected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective onthe epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasmamembrane permeability and on mammalian cell viability was tested, and no change wasobserved. Autophagosomes and apoptotic bodies were detected as part of the mechanismsof isotretinoin-induced death indicating that the inhibition of transporters by isotretinoincauses nutrient starvation that triggers autophagic and apoptotic processes. In conclusion,isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essentialmetabolites transporters, in addition to being an FDA-approved drug largely used inhumans, which could reduce significantly the requirements for its possible application in thetreatment of Chagas disease.