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Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4694730
Author(s)
Rao, S. P. S.; Gould, M. K.; Noeske, J.; Saldivia, M.; Jumani, R. S.; Ng, P. S.; Rene, 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.; Diagana, T. T.
Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections
Journal
Science
Volume
380
Number
6652
Pages / Article-Number
1349-1356
Keywords
Humans; Animals; Mice; *Poisons; DNA Topoisomerases, Type II; Cryoelectron Microscopy; *Trypanosoma; *Chagas Disease/drug therapy; Multienzyme Complexes
Mesh terms
Animals; Humans; Mice; Chagas Disease, drug therapy; Cryoelectron Microscopy; DNA Topoisomerases, Type II, metabolism; Trypanosoma, drug effects; Topoisomerase II Inhibitors, therapeutic use; Triazoles, therapeutic use; Trypanosomiasis, African, drug therapy; Drug Evaluation, Preclinical
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.
