Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Rao, S. P. S. et al. (2023) Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science, 380(6652), pp. 1349-1356. (doi: 10.1126/science.adh0614) (PMID:37384702)

Full text not currently available from Enlighten.


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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Barrett, Professor Michael and Ritchie, Mr Ryan and Gould, Matthew
Authors: Rao, S. P. S., Gould, M. K., Noeske, J., Saldivia, M., Jumani, R. S., Ng, P. S., René, O., Chen, Y.-L., Kaiser, M., Ritchie, R., Francisco, A. F., Johnson, N., Patra, D., Cheung, H., Deniston, C., Schenk, A. D., Cortopassi, W. A., Schmidt, R. S., Wiedemar, N., Thomas, B., Palkar, R., Ghafar, N. A., Manoharan, V., Luu, C., Gable, J. E., Wan, K. F., Myburgh, E., Mottram, J. C., Barnes, W., Walker, J., Wartchow, C., Aziz, N., Osborne, C., Wagner, J., Sarko, C., Kelly, J. M., Manjunatha, U. H., Mäser, P., Jiricek, J., Lakshminarayana, S. B., Barrett, M. P., and Diagana, T. T.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Science
Publisher:American Association for the Advancement of Science
ISSN (Online):1095-9203
Published Online:29 June 2023
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190800In vivo screening resource to support drug development in parasitic diseaseJeremy MottramWellcome Trust (WELLCOTR)104976/Z14/ZSII - Parasitology
304784Bridging epigenetic, metabolism and cell cycle in pathogenic trypanosomatidsMichael BarrettMedical Research Council (MRC)MR/S019650/1SII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZSII - Parasitology