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)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 0036-8075 |
| ISSN (Online): | 1095-9203 |
| Published Online: | 29 June 2023 |
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