Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.
;
Matthew K
Gould
;
Jonas
Noeske
;
Manuel
Saldivia
;
Rajiv S
Jumani
;
Pearly S
Ng
;
Olivier
René
;
Yen-Liang
Chen
;
Marcel
Kaiser
;
Ryan
Ritchie
;
+32 more...
Amanda Fortes
Francisco
;
Nila
Johnson
;
Debjani
Patra
;
Harry
Cheung
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Colin
Deniston
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Andreas D
Schenk
;
Wilian A
Cortopassi
;
Remo S
Schmidt
;
Natalie
Wiedemar
;
Bryanna
Thomas
;
Rima
Palkar
;
Nahdiyah A
Ghafar
;
Vanessa
Manoharan
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Catherine
Luu
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Jonathan E
Gable
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Kah Fei
Wan
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Elmarie
Myburgh
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Jeremy C
Mottram
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Whitney
Barnes
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John
Walker
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Charles
Wartchow
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Natasha
Aziz
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Colin
Osborne
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Juergen
Wagner
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Christopher
Sarko
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John M
Kelly
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Ujjini H
Manjunatha
;
Pascal
Mäser
;
Jan
Jiricek
;
Suresh B
Lakshminarayana
;
Michael P
Barrett
;
Thierry T
Diagana
;
(2023)
Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.
Science, 380 (6652).
pp. 1349-1356.
ISSN 0036-8075
DOI: 10.1126/science.adh0614
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.
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picture_as_pdf - Rao-etal-2023-Cyanotriazoles-are-selective-topoisomerase-ii.pdf
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subject - Accepted Version
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- Available under Creative Commons: Attribution-NonCommercial-No Derivative Works 4.0