Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Srinivasa P S Rao; Matthew K Gould; Jonas Noeske; Manuel Saldivia; Rajiv S Jumani; Pearly S Ng; Olivier René; Yen-Liang Chen; Marcel Kaiser; Ryan Ritchie; Amanda Fortes Francisco; Nila Johnson; Debjani Patra; Harry Cheung; Colin Deniston; Andreas D Schenk; Wilian A Cortopassi; Remo S Schmidt; Natalie Wiedemar; Bryanna Thomas; Rima Palkar; Nahdiyah A Ghafar; Vanessa Manoharan; Catherine Luu; Jonathan E Gable; Kah Fei Wan; Elmarie Myburgh; Jeremy C Mottram; Whitney Barnes; John Walker; Charles Wartchow; Natasha Aziz; Colin Osborne; Juergen Wagner; Christopher Sarko; John M Kelly; Ujjini H Manjunatha; Pascal Mäser; Jan Jiricek; Suresh B Lakshminarayana; Michael P Barrett; Thierry T Diagana

doi:10.1126/science.adh0614

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Srinivasa P S Rao, Matthew K Gould, Jonas Noeske, Manuel Saldivia, Rajiv S Jumani, Pearly S Ng, Olivier René, Yen-Liang Chen, Marcel Kaiser, Ryan Ritchie, Amanda Fortes Francisco, Nila Johnson, Debjani Patra, Harry Cheung, Colin Deniston, Andreas D Schenk, Wilian A Cortopassi, Remo S Schmidt, Natalie Wiedemar, Bryanna ThomasRima Palkar, Nahdiyah A Ghafar, Vanessa Manoharan, Catherine Luu, Jonathan E Gable, Kah Fei Wan, Elmarie Myburgh, Jeremy C Mottram, Whitney Barnes, John Walker, Charles Wartchow, Natasha Aziz, Colin Osborne, Juergen Wagner, Christopher Sarko, John M Kelly, Ujjini H Manjunatha, Pascal Mäser, Jan Jiricek, Suresh B Lakshminarayana, Michael P Barrett, Thierry T Diagana

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1349-1356
Number of pages	8
Journal	Science (New York, N.Y.)
Volume	380
Issue number	6652
DOIs	https://doi.org/10.1126/science.adh0614
Publication status	Published - 29 Jun 2023

Bibliographical note

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

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Rao2023_AuthorAcceptedManuscript
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Cite this

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., ... Diagana, T. T. (2023). Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science (New York, N.Y.), 380(6652), 1349-1356. https://doi.org/10.1126/science.adh0614

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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.",

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Rao, SPS, Gould, MK, Noeske, J, Saldivia, M, Jumani, RS, Ng, PS, René, O, Chen, Y-L, Kaiser, M, Ritchie, R, Francisco, AF, Johnson, N, Patra, D, Cheung, H, Deniston, C, Schenk, AD, Cortopassi, WA, Schmidt, RS, Wiedemar, N, Thomas, B, Palkar, R, Ghafar, NA, Manoharan, V, Luu, C, Gable, JE, Wan, KF, Myburgh, E , Mottram, JC, Barnes, W, Walker, J, Wartchow, C, Aziz, N, Osborne, C, Wagner, J, Sarko, C, Kelly, JM, Manjunatha, UH, Mäser, P, Jiricek, J, Lakshminarayana, SB, Barrett, MP & Diagana, TT 2023, 'Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections', Science (New York, N.Y.), vol. 380, no. 6652, pp. 1349-1356. https://doi.org/10.1126/science.adh0614

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AU - Gould, Matthew K

AU - Noeske, Jonas

AU - Saldivia, Manuel

AU - Jumani, Rajiv S

AU - Ng, Pearly S

AU - René, Olivier

AU - Chen, Yen-Liang

AU - Kaiser, Marcel

AU - Ritchie, Ryan

AU - Francisco, Amanda Fortes

AU - Johnson, Nila

AU - Patra, Debjani

AU - Cheung, Harry

AU - Deniston, Colin

AU - Schenk, Andreas D

AU - Cortopassi, Wilian A

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AU - Wiedemar, Natalie

AU - Thomas, Bryanna

AU - Palkar, Rima

AU - Ghafar, Nahdiyah A

AU - Manoharan, Vanessa

AU - Luu, Catherine

AU - Gable, Jonathan E

AU - Wan, Kah Fei

AU - Myburgh, Elmarie

AU - Mottram, Jeremy C

AU - Barnes, Whitney

AU - Walker, John

AU - Wartchow, Charles

AU - Aziz, Natasha

AU - Osborne, Colin

AU - Wagner, Juergen

AU - Sarko, Christopher

AU - Kelly, John M

AU - Manjunatha, Ujjini H

AU - Mäser, Pascal

AU - Jiricek, Jan

AU - Lakshminarayana, Suresh B

AU - Barrett, Michael P

AU - Diagana, Thierry T

N1 - 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.

PY - 2023/6/29

Y1 - 2023/6/29

N2 - 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.

AB - 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.

KW - Humans

KW - Animals

KW - Mice

KW - Poisons

KW - DNA Topoisomerases, Type II

KW - Cryoelectron Microscopy

KW - Trypanosoma

KW - Chagas Disease/drug therapy

KW - Multienzyme Complexes

U2 - 10.1126/science.adh0614

DO - 10.1126/science.adh0614

M3 - Article

C2 - 37384702

SN - 0036-8075

VL - 380

SP - 1349

EP - 1356

JO - Science

JF - Science

IS - 6652

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