IID432, a parasite-selective topoisomerase II inhibitor, achieves rapid single-dose parasite clearance in a murine chronic Chagas model

Chagas disease is a neglected disease that affects millions of people from the Latin American region. Current nitroheterocyclic therapies suffer from long treatment duration and safety-related treatment discontinuations. A safe, short course therapy would significantly benefit Chagas patients. Here, we report the comprehensive biological, structural, pharmacodynamic, and pharmacokinetic characterization of IID432, an optimized cyanotriazole with superior potency, favorable pharmacokinetics, and improved safety profile compared to the lead compound CT1. IID432 is a fast-acting, parasite-selective topoisomerase II poison that achieves sterile cure after a single oral dose in a murine model of chronic Trypanosoma cruzi infection. Mechanistically, IID432 stabilizes the parasite TcTopoII-DNA cleavage complex by covalently engaging a parasite-specific cysteine (Cys477), thereby conferring selectivity over the human TOP2A. IID432 displays favorable oral pharmacokinetics, with no off-target activity on human topoisomerases. Brief exposure of IID432 rapidly induces parasite-specific DNA damage and produces sterilizing activity in vitro and in vivo without recrudescence. Together, these findings identify IID432 as a first-in-class, parasite-selective covalent topoisomerase poison with a potential to significantly shorten treatment duration for T. cruzi infections.