Supplementary information files for "Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease"

Supplementary files for article ""Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease"<br><br><b>One Sentence Summary:</b> Quinazolines targeting lysyl tRNA synthase show partial efficacy in a mouse model of Chagas<br><b>Accessible Summary:</b> New drugs are required to treat Chagas disease, a deadly parasitic infection prevalent in Latin America. Here, Tulloch et al. investigate the mechanism of action of a new series of quinazoline compounds demonstrating potential against Trypanosoma cruzi, the causative agent of Chagas disease. Genetic, biochemical and proteomics approaches identify the molecular target of these compounds as lysyl-tRNA-synthetase-1. The lead compound from the series is partially efficacious in a model of acute Chagas disease thus identifying T. cruzi lysyl-tRNA-synthetase-1 as a viable drug target. However, this quinazoline series will require further development to become a future treatment for this neglected disease.<b>Abstract:</b> The protozoan parasite <i>Trypanosoma cruzi</i> causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against <i>Trypanosoma cruzi</i> and the related trypanosomatid parasites <i>Trypanosoma brucei</i> and <i>Leishmania donovani</i>. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of <i>T. cruzi</i> lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating <i>T. cruzi</i> infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.<br><br>© The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. CC BY-NC-ND 4.0