Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo–electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease. Description Editor’s summary Treatments for diseases caused by trypanosomatid parasites, including Chagas disease and African sleeping sickness, remain a crucial unmet medical need for millions of people globally. Rao et al. identified and characterized a cyanotriazole compound class that was able to kill trypanosomes by selective inhibition of the parasite topoisomerase II enzyme (see the Perspective by Aphasizhev and Aphasizheva). Cryo–electron microscopy revealed that cyanotriazoles poison the parasite topoisomerase, thereby causing irreversible and lethal DNA damage. This mechanism led to rapid clearance of parasites both in vitro and in mouse models of Chagas disease and sleeping sickness. Cyanotriazole treatment has the potential to improve therapies for these neglected diseases. —Stella M. Hurtley A class of cyanotriazole drugs that provide fast-acting trypanosomatid-specific topoisomerase II inhibitors was identified.