Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections-Reference-Cited by-同舟云学术

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections

Published:2023-06-30 Issue:6652 Volume:380 Page:1349-1356
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Rao Srinivasa P. S.¹²³^ORCID,Gould Matthew K.⁴^ORCID,Noeske Jonas²^ORCID,Saldivia Manuel¹²^ORCID,Jumani Rajiv S.¹²^ORCID,Ng Pearly S.³^ORCID,René Olivier¹²,Chen Yen-Liang¹²³^ORCID,Kaiser Marcel⁵⁶^ORCID,Ritchie Ryan⁴^ORCID,Francisco Amanda Fortes⁷^ORCID,Johnson Nila¹,Patra Debjani¹²,Cheung Harry¹²,Deniston Colin⁸^ORCID,Schenk Andreas D.⁹^ORCID,Cortopassi Wilian A.²^ORCID,Schmidt Remo S.⁵⁶^ORCID,Wiedemar Natalie⁵⁶^ORCID,Thomas Bryanna¹²,Palkar Rima¹^ORCID,Ghafar Nahdiyah A.³^ORCID,Manoharan Vanessa³,Luu Catherine²^ORCID,Gable Jonathan E.¹²,Wan Kah Fei³^ORCID,Myburgh Elmarie¹⁰^ORCID,Mottram Jeremy C.¹¹^ORCID,Barnes Whitney⁸^ORCID,Walker John⁸^ORCID,Wartchow Charles²^ORCID,Aziz Natasha¹²^ORCID,Osborne Colin¹²^ORCID,Wagner Juergen³⁹^ORCID,Sarko Christopher¹²^ORCID,Kelly John M.⁷^ORCID,Manjunatha Ujjini H.¹²³^ORCID,Mäser Pascal⁵⁶^ORCID,Jiricek Jan¹³,Lakshminarayana Suresh B.¹²³^ORCID,Barrett Michael P.⁴^ORCID,Diagana Thierry T.¹²³^ORCID

Affiliation:

1. Novartis Institute for Tropical Diseases, Emeryville, CA, USA.

2. Novartis Institutes for BioMedical Research, Emeryville, CA, USA.

3. Novartis Institute for Tropical Diseases, Singapore.

4. College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

5. Swiss Tropical and Public Health Institute, Allschwil, Switzerland.

6. Faculty of Science, University of Basel, Basel, Switzerland.

7. London School of Hygiene and Tropical Medicine, London, UK.

8. Novartis Institutes for BioMedical Research, San Diego, CA, USA.

9. Novartis Institutes for BioMedical Research, Basel, Switzerland.

10. York Biomedical Research Institute, Hull York Medical School, University of York, York, UK.

11. York Biomedical Research Institute, Department of Biology, University of York, York, UK.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.adh0614

Reference50 articles.

1. Chagas disease

2. Human African trypanosomiasis

3. Leishmaniasis

4. Cutaneous leishmaniasis

5. New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

Cited by 9 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. High-throughput screening of compounds targeting RNA editing in Trypanosoma brucei: Novel molecular scaffolds with broad trypanocidal effects;Biochemical Pharmacology;2024-01

2. Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice;PLOS Pathogens;2023-11-13

3. UCSF ChimeraX: Tools for structure building and analysis;Protein Science;2023-10-20

4. A Fluorescence-Based, T5 Exonuclease-Amplified DNA Cleavage Assay for Discovering Bacterial DNA Gyrase Poisons;2023-10-16

5. An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials;Frontiers in Parasitology;2023-10-09