Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Rao, S. P. S. and Gould, M. K. and Noeske, J. and Saldivia, M. and Jumani, R. S. and Ng, P. S. and Rene, O. and Chen, Y. L. and Kaiser, M. and Ritchie, R. and Francisco, A. F. and Johnson, N. and Patra, D. and Cheung, H. and Deniston, C. and Schenk, A. D. and Cortopassi, W. A. and Schmidt, R. S. and Wiedemar, N. and Thomas, B. and Palkar, R. and Ghafar, N. A. and Manoharan, V. and Luu, C. and Gable, J. E. and Wan, K. F. and Myburgh, E. and Mottram, J. C. and Barnes, W. and Walker, J. and Wartchow, C. and Aziz, N. and Osborne, C. and Wagner, J. and Sarko, C. and Kelly, J. M. and Manjunatha, U. H. and Mäser, P. and Jiricek, J. and Lakshminarayana, S. B. and Barrett, M. P. and Diagana, T. T.. (2023) Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science, 380 (6652). pp. 1349-1356.

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Official URL: https://edoc.unibas.ch/95320/

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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.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:	Mäser, Pascal and Kaiser, Marcel
Item Type:	Article, refereed
Article Subtype:	Research Article
ISSN:	0036-8075
Note:	Publication type according to Uni Basel Research Database: Journal article
Identification Number:	doi: 10.1126/science.adh0614 pmid: 37384702
Last Modified:	23 Oct 2023 14:34
Deposited On:	23 Oct 2023 14:34

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