Lindsay B. Tulloch, Hugh Tawell, Annie E. Taylor, Marta Lopes Lima , Alice Dawson , Sandra Carvalho, Richard J. Wall, Victoriano Corpas-Lopez, Gourav Dey, Jack Duggan , Luma Godoy Magalhaes, Leah S. Torrie, Laura Frame, David Robinson , Stephen Patterson, Michele Tinti , George W. Weaver, William J. Robinson, Monica Cal , Marcel Kaiser, Pascal Mäser, Peter Sjö, Benjamin Perry, John M. Kelly, Amanda Fortes Francisco , Avninder S. Bhambra, and Susan Wyllie
Sci. Transl. Med.17,eadu4564(2025).
The protozoan parasite Trypanosoma cruzi 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 Trypanosoma cruzi and the related trypanosomatid parasites Trypanosoma brucei and Leishmania donovani. 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 T. cruzi 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 T. cruzi 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.