Discovery, target identification and lead optimisation of a quinazoline series with potent anti-Chagasic activity

We next used an approach to determine the direct binding of quinazolines to their target(s). A protein can be stabilised or destabilised through the binding of a ligand, altering that proteins thermostability. Such alterations in thermostability can cause a ligated protein to denature at a different temperature from its unligated counterpart (Corpas-Lopez and Wyllie, 2021; Paradela et al., 2021; Lima et al., 2022; Milne et al., 2022; Hanna et al., 2023). Isothermal proteome profiling (IPP), which detects changes in protein thermostability following the addition of drug to a lysate, was used to determine which proteins from the entire T. cruzi proteome bind to Q371 and Bhambra-10.3.