Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections
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.
| Errataetall: |
CommentIn: Nat Rev Drug Discov. 2023 Sep;22(9):694. - PMID 37468690 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:380 |
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| Enthalten in: |
Science (New York, N.Y.) - 380(2023), 6652 vom: 30. Juni, Seite 1349-1356 |
| Sprache: |
Englisch |
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| Themen: |
DNA Topoisomerases, Type II |
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Date Completed 11.07.2023 Date Revised 14.02.2024 published: Print-Electronic CommentIn: Nat Rev Drug Discov. 2023 Sep;22(9):694. - PMID 37468690 Citation Status MEDLINE |
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| doi: |
10.1126/science.adh0614 |
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| 520 | |a 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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