Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.

Abstract

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.