by Tulloch LB, Tawell H, Taylor AE, Lopes Lima L, Dawson A, Carvalho S, Wall RJ, Corpas-Lopez V, Dey G, Duggan J, Godoy Magalhaes L, Torrie LS, Frame L, Robinson D, Patterson S, Tinti M, Weaver GW, Robinson WJ, Cal M, Kaiser M, Mäser P, Sjö P, Perry B, Kelly JM, Fortes Francisco A, Bhambra AS, Wyllie S. Science Translational Medicine 2025, 17: eadu4564. doi: 10.1126/scitranslmed.adu4564.
Summary: The authors of this manuscript describe a previously unidentified series of quinazoline compounds with potential against Trypanosoma cruzi, the causative agent of Chagas disease, and the related trypanosomatid parasites Trypanosoma brucei and Leishmania donovani. They demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies showed that this series targeted the ATP-binding pocket of T. cruzi lysyl-tRNA synthetase 1 (KRS1). This 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 requires further development.
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