Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

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.

Metadata

Item Type:	Article
Authors/Creators:	Rao, Srinivasa P S Gould, Matthew K Noeske, Jonas Saldivia, Manuel Jumani, Rajiv S Ng, Pearly S René, 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 https://orcid.org/0000-0002-2007-5902 Mottram, Jeremy C https://orcid.org/0000-0001-5574-3766 Barnes, Whitney Walker, John Wartchow, Charles Aziz, Natasha Osborne, Colin Wagner, Juergen Sarko, Christopher Kelly, John M Manjunatha, Ujjini H Mäser, Pascal Jiricek, Jan Lakshminarayana, Suresh B Barrett, Michael P Diagana, Thierry T
Copyright, Publisher and Additional Information:	This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Keywords:	Humans,Animals,Mice,Poisons,DNA Topoisomerases, Type II,Cryoelectron Microscopy,Trypanosoma,Chagas Disease/drug therapy,Multienzyme Complexes
Dates:	Published: 29 June 2023 Accepted: 24 May 2023 Submitted: 22 February 2023
Institution:	The University of York
Academic Units:	The University of York > Faculty of Sciences (York) > Hull York Medical School (York) The University of York > Faculty of Sciences (York) > Biology (York)
Depositing User:	Pure (York)
Date Deposited:	20 Oct 2023 15:00
Last Modified:	22 Nov 2024 00:44
Published Version:	https://doi.org/10.1126/science.adh0614
Status:	Published
Refereed:	Yes
Identification Number:	10.1126/science.adh0614
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:204462

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Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

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