8gcc
T. cruzi topoisomerase II alpha bound to dsDNA and the covalent inhibitor CT1
Structural highlights
FunctionQ4DE53_TRYCC Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.[RuleBase:RU362094] Publication Abstract from PubMedMillions 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. Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.,Rao SPS, Gould MK, Noeske J, Saldivia M, Jumani RS, Ng PS, Rene O, Chen YL, 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, Maser P, Jiricek J, Lakshminarayana SB, Barrett MP, Diagana TT Science. 2023 Jun 30;380(6652):1349-1356. doi: 10.1126/science.adh0614. Epub 2023 , Jun 29. PMID:37384702[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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