Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.

Autor: Rao SPS; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore., Gould MK; College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Noeske J; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Saldivia M; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Jumani RS; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Ng PS; Novartis Institute for Tropical Diseases, Singapore., René O; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Chen YL; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore., Kaiser M; Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; Faculty of Science, University of Basel, Basel, Switzerland., Ritchie R; College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Francisco AF; London School of Hygiene and Tropical Medicine, London, UK., Johnson N; Novartis Institute for Tropical Diseases, Emeryville, CA, USA., Patra D; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Cheung H; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Deniston C; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Schenk AD; Novartis Institutes for BioMedical Research, Basel, Switzerland., Cortopassi WA; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Schmidt RS; Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; Faculty of Science, University of Basel, Basel, Switzerland., Wiedemar N; Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; Faculty of Science, University of Basel, Basel, Switzerland., Thomas B; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Palkar R; Novartis Institute for Tropical Diseases, Emeryville, CA, USA., Ghafar NA; Novartis Institute for Tropical Diseases, Singapore., Manoharan V; Novartis Institute for Tropical Diseases, Singapore., Luu C; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Gable JE; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Wan KF; Novartis Institute for Tropical Diseases, Singapore., Myburgh E; York Biomedical Research Institute, Hull York Medical School, University of York, York, UK., Mottram JC; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Barnes W; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Walker J; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Wartchow C; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Aziz N; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Osborne C; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Wagner J; Novartis Institute for Tropical Diseases, Singapore.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Sarko C; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Kelly JM; London School of Hygiene and Tropical Medicine, London, UK., Manjunatha UH; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore., Mäser P; Swiss Tropical and Public Health Institute, Allschwil, Switzerland.; Faculty of Science, University of Basel, Basel, Switzerland., Jiricek J; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore., Lakshminarayana SB; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore., Barrett MP; College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Diagana TT; Novartis Institute for Tropical Diseases, Emeryville, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA.; Novartis Institute for Tropical Diseases, Singapore.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Jun 30; Vol. 380 (6652), pp. 1349-1356. Date of Electronic Publication: 2023 Jun 29.
DOI: 10.1126/science.adh0614
Abstrakt: 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.
Databáze: MEDLINE
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