Identification of new inhibitors of the arginine transporter TcAAP3 from Trypanosoma cruzi through an in silico strategy

GALCERAN, FACUNDO; DIGIROLAMO FABIO; MACIEL, BELEN; RENGIFO, MARCOS; PEREIRA, CA; SAYE, MELISA; REIGADA, CHANTAL; MIRANDA, MARIANA

Montevideo

Conferencia; NTD Network Early Career Researcher Conference 2022; 2022

A Global Network for Neglected Tropical Diseases

Trypanosoma cruzi is the causative agent of Chagas disease, whichaffects almost 7 million people mainly in Latin America. Theparasite metabolism is widely based on amino acid consumption,both as alternative carbon and energy sources and as energyreservoirs. The amino acid arginine can be converted tophosphoarginine through a reversible reaction catalyzed byarginine kinase (AK): arginine + ATP P-arginine + ADP.Overexpression of arginine transporter TcAAP3 augmentsintracellular arginine and induces AK downregulation tocompensate the increase in ATP consumption suggesting that T.cruzi?s viability can be affected through fluctuations in arginineuptake. Additionally, essentiality of arginine permease TbAAT5from T. brucei, orthologous to TcAAP3, has been proved throughRNAi assays.In this work we identify potential TcAAP3 inhibitors that may alsohave trypanocidal effect on T. cruzi. L-arginine was used astemplate molecule in a similarity-based virtual screening applied to320,000 query compounds, including worldwide approved drugsand natural products among others. After thorough inspection, 45compounds were selected for molecular docking assays. Since the3D structure of the arginine transporter TcAAP3 is not available, wegenerated and refined a homology-based model using the crystalstructure of the neutral amino acid transporter SLC38A9 (PDB7KGV) as template. Next, molecular docking assays wereperformed to predict the binding of the potential inhibitors with theTcAAP3 model. From these results, 5 compounds were selected forin vitro assays, and are currently under evaluation as TcAAP3inhibitors and as trypanocidal drugs. The 5 compounds selected areiobenguane, sulfaguanidine, isotretinoin, assymetricdimethylarginine and aminohippuric acid. Using a similar approachwe have identified inhibitors of the proline and the polyaminestransporters TcAAAP069 and TcPAT12 with trypanocidal action.New therapies are needed to treat Chagas disease and computeraided strategies allow the rapid identification of drug candidates.