Cyanotriazole compounds are fast-acting topoisomerase II poisons that may selectively and rapidly kill trypanosome parasites that cause Chagas disease and African sleeping sickness, in keeping with a recent study.

Tens of millions who live in Latin America and sub-Saharan Africa are in danger for trypanosomatid infections – pathogenic protozoan parasites that cause Chagas disease and human African trypanosomiasis (HAT), that are potentially fatal if not treated. Although treatments for HAT have improved lately, Chagas therapies remain limited and depend on lengthy regimens of toxic drugs. More practical, safer, and shorter-duration therapeutics for Chagas disease are critically needed.

Here, Srinivasa Rao and colleagues performed an automatic whole-cell high-throughput screening of the Novartis compound library – a database of drug-like molecules – to find potential growth inhibitors for trypanosomatids. Through this evaluation, Rao et al. identified a category of cyanotriazoles (CTs), which exhibited potent trypanocidal activity and led to rapid clearance of parasites each in vitro and in mouse models of Chagas and HAT.

Using cryo-electron microscopy, the authors discovered that CTs selectively poison the parasite’s topoisomerase II – a vital enzyme in DNA replication – causing irreversible and lethal DNA damage. “Given their therapeutic efficacy, we’re undertaking advanced preclinical profiling of further optimized CT analogs to discover clinical candidates with an acceptable safety profile,” write Rao et al. In a related Perspective Ruslan Aphasizhev and Inna Aphasizheva discuss the study and its findings in additional detail.

Source:

American Association for the Advancement of Science (AAAS)

Journal reference:

Rao, S. P. S., et al. (2023) Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science. doi.org/10.1126/science.adh0614.