2. Academic Validation
  3. Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

  • Science. 2023 Jun 30;380(6652):1349-1356. doi: 10.1126/science.adh0614.
Srinivasa P S Rao 1 2 3,  Matthew K Gould 4,  Jonas Noeske 2,  Manuel Saldivia 1 2,  Rajiv S Jumani 1 2,  Pearly S Ng 3,  Olivier René 1 2,  Yen-Liang Chen 1 2 3,  Marcel Kaiser 5 6,  Ryan Ritchie 4,  Amanda Fortes Francisco 7,  Nila Johnson 1,  Debjani Patra 1 2,  Harry Cheung 1 2,  Colin Deniston 8,  Andreas D Schenk 9,  Wilian A Cortopassi 2,  Remo S Schmidt 5 6,  Natalie Wiedemar 5 6,  Bryanna Thomas 1 2,  Rima Palkar 1,  Nahdiyah A Ghafar 3,  Vanessa Manoharan 3,  Catherine Luu 2,  Jonathan E Gable 1 2,  Kah Fei Wan 3,  Elmarie Myburgh 10,  Jeremy C Mottram 11,  Whitney Barnes 8,  John Walker 8,  Charles Wartchow 2,  Natasha Aziz 1 2,  Colin Osborne 1 2,  Juergen Wagner 3 9,  Christopher Sarko 1 2,  John M Kelly 7,  Ujjini H Manjunatha 1 2 3,  Pascal Mäser 5 6,  Jan Jiricek 1 3,  Suresh B Lakshminarayana 1 2 3,  Michael P Barrett 4,  Thierry T Diagana 1 2 3
Affiliations

Affiliations

  • 1 Novartis Institute for Tropical Diseases, Emeryville, CA, USA.
  • 2 Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
  • 3 Novartis Institute for Tropical Diseases, Singapore.
  • 4 College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • 5 Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
  • 6 Faculty of Science, University of Basel, Basel, Switzerland.
  • 7 London School of Hygiene and Tropical Medicine, London, UK.
  • 8 Novartis Institutes for BioMedical Research, San Diego, CA, USA.
  • 9 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 10 York Biomedical Research Institute, Hull York Medical School, University of York, York, UK.
  • 11 York Biomedical Research Institute, Department of Biology, University of York, York, UK.
PMID: 37384702 DOI: 10.1126/science.adh0614
Abstract

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.

Figures
Products