Two Targets, One Parasite: Designing Selective Covalent Inhibitors for Chagas Disease

Chagas Disease, caused by the protozoan parasite Trypanosoma cruzi, affects millions worldwide, yet current therapies suffer from limited efficacy, long treatment duration, and poor tolerability. Two complementary discovery strategies, one mechanism-driven and one phenotypically guided, were explored toward safer, shorter-course treatments. Covalent picolinamides were developed as highly selective inhibitors of the essential T. cruzi kinase CLK1, achieving potent cellular activity and cures in mouse infections models. In parallel, covalent cyanotriazoles were optimized into IID432, a selective T. cruzi topoisomerase II poison capable of delivering an unprecedented single-dose cure in vivo and now advancing toward clinical evaluation. Together, these strategies illustrate how mechanistic insight and covalent design can enable next-generation therapies for Chagas Disease.

Speaker: Olivier René, Novartis