In silico identification and in vitro evaluation of potential inhibitors of the arginine transporter TcAAP3 from Trypanosoma cruzi

MACIEL, BELEN; REIGADA, CHANTAL; MIRANDA, MARIANA R.; GALCERAN, FACUNDO; DIGIROLAMO, FABIO; SAYÉ, MELISA; RENGIFO, MARCOS; PEREIRA, CLAUDIO A.

Woods hole

Congreso; Molecular Parasitology Meeting MPM XXXIII; 2022

Marine biological laboratory

Trypanosoma cruzi is the causative agent of Chagas disease, which affects almost 7million people mainly in Latin America. The parasite metabolism is widely based onamino acid consumption, both as alternative carbon and energy sources and as energyreservoirs. The amino acid arginine can be converted to phosphoarginine through areversible reaction catalyzed by arginine kinase (AK): arginine + ATP P-arginine +ADP. Overexpression of arginine transporter TcAAP3 augments intracellular arginineand induces AK downregulation to compensate the increase in ATP consumptionsuggesting that T. cruzi?s viability can be affected through fluctuations in arginineuptake. Additionally, essentiality of arginine permease from T. brucei, orthologous toTcAAAP3, has been proved through RNAi assays. In this work we identified potentialTcAAP3 inhibitors that may also have trypanocidal effect on T. cruzi. L-arginine wasused as template molecule in a similarity-based virtual screening applied to 320,000query compounds, including worldwide approved drugs for human use among others.After thorough inspection, 45 compounds were selected for molecular docking assayswith the 3D structure of TcAAP3 that we generated by homology modeling. Fivecompounds docked in the same region as arginine and presented better predictedbinding energies than arginine itself. After in vitro evaluation of these compounds, onlythe drug isotretinoin, which is used to treat severe acne, was able to inhibit arginineuptake and also had trypanocidal activity in T. cruzi. New therapies are needed to treatChagas disease and computer-aided strategies allow the rapid identification of drugcandidates.