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

MACIEL BJ; MARTÍNEZ SAYÉ M; GALCERAN F; REIGADA C; RENGIFO M; DI GIROLAMO F; MIRANDA MR; PEREIRA CA

Congreso; XXXIII Molecular Parasitology Meeting; 2022

Marine Biology Laboratory Woods Hole

Trypanosoma cruzi is the causative agent of Chagas disease, which affects almost 7 million people mainly in Latin America. The parasite metabolism is widely based on amino acid consumption, both as alternative carbon and energy sources and as energy reservoirs. The amino acid arginine can be converted to phosphoarginine through a reversible reaction catalyzed by arginine kinase (AK): arginine + ATP P-arginine + ADP. Overexpression of arginine transporter TcAAP3 augments intracellular arginine and induces AK downregulation to compensate the increase in ATP consumption suggesting that T. cruzi’s viability can be affected through fluctuations in arginine uptake. Additionally, essentiality of arginine permease from T. brucei, orthologous to TcAAAP3, has been proved through RNAi assays. In this work we identified potential TcAAP3 inhibitors that may also have trypanocidal effect on T. cruzi. L-arginine was used as template molecule in a similarity-based virtual screening applied to 320,000 query compounds, including worldwide approved drugs for human use among others. After thorough inspection, 45 compounds were selected for molecular docking assays with the 3D structure of TcAAP3 that we generated by homology modeling. Five compounds docked in the same region as arginine and presented better predicted binding energies than arginine itself. After in vitro evaluation of these compounds, only the drug isotretinoin, which is used to treat severe acne, was able to inhibit arginine uptake and also had trypanocidal activity in T. cruzi. New therapies are needed to treatChagas disease and computer-aided strategies allow the rapid identification of drug candidates.