Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Srinivasa P S Rao, Matthew K Gould, Jonas Noeske, Manuel Saldivia, Rajiv S Jumani, Pearly S Ng, Olivier René, Yen-Liang Chen, Marcel Kaiser, Ryan Ritchie, Amanda Fortes Francisco, Nila Johnson, Debjani Patra, Harry Cheung, Colin Deniston, Andreas D Schenk, Wilian A Cortopassi, Remo S Schmidt, Natalie Wiedemar, Bryanna ThomasRima Palkar, Nahdiyah A Ghafar, Vanessa Manoharan, Catherine Luu, Jonathan E Gable, Kah Fei Wan, Elmarie Myburgh, Jeremy C Mottram, Whitney Barnes, John Walker, Charles Wartchow, Natasha Aziz, Colin Osborne, Juergen Wagner, Christopher Sarko, John M Kelly, Ujjini H Manjunatha, Pascal Mäser, Jan Jiricek, Suresh B Lakshminarayana, Michael P Barrett, Thierry T Diagana

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1349-1356
Number of pages8
JournalScience (New York, N.Y.)
Issue number6652
Publication statusPublished - 29 Jun 2023

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  • Humans
  • Animals
  • Mice
  • Poisons
  • DNA Topoisomerases, Type II
  • Cryoelectron Microscopy
  • Trypanosoma
  • Chagas Disease/drug therapy
  • Multienzyme Complexes

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