Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

• 成果类型: Article
• 署名作者: Rao, Srinivasa P. S.; Gould, Matthew K.; Noeske, Jonas; Saldivia, Manuel; Jumani, Rajiv S.; Ng, Pearly S.; Rene, Olivier; Chen, Yen-Liang; Kaiser, Marcel; Ritchie, Ryan; Francisco, Amanda Fortes; Johnson, Nila; Patra, Debjani; Cheung, Harry; Deniston, Colin; Schenk, Andreas D.; Cortopassi, Wilian A.; Schmidt, Remo S.; Wiedemar, Natalie; Thomas, Bryanna; Palkar, Rima; Ghafar, Nahdiyah A.; Manoharan, Vanessa; Luu, Catherine; Gable, Jonathan E.; Wan, Kah Fei; Myburgh, Elmarie; Mottram, Jeremy C.; Barnes, Whitney; Walker, John; Wartchow, Charles; Aziz, Natasha; Osborne, Colin; Wagner, Juergen; Sarko, Christopher; Kelly, John M.; Manjunatha, Ujjini H.; Maeser, Pascal; Jiricek, Jan; Lakshminarayana, Suresh B.; Barrett, Michael P.; Diagana, Thierry T.
• 署名单位: Novartis; Novartis USA; Novartis; Novartis Singapore; University of Glasgow; University of Basel; Swiss Tropical & Public Health Institute; University of Basel; University of London; London School of Hygiene & Tropical Medicine; Novartis; Novartis USA; Novartis; University of Hull; University of York - UK; University of York - UK
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12306
• DOI: 10.1126/science.adh0614
• 发表日期: 2023-06-30
• 页码: 1349-1356
• 关键词: posaconazole; mechanism; cleavage; reveals; disease; complex; target; ia

摘要

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.