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A click chemistry-based artificial metallo-nuclease

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posted on 2024-10-23, 14:12 authored by Alex Gibney, Raphael E. F. de Paiva, Vandana Singh, Robert Fox, Damien ThompsonDamien Thompson, Joseph Hennessy, Creina Slator, Christine J. McKenzie, Pegah Johansson, Vickie Mckee, Fredrik Westerlund, Andrew Kellett

Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C3-symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII-TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.

Funding

SSPC_Phase 2

Science Foundation Ireland

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Nucleic Acids for Future Gene Editing, Immunotherapy and Epigenetic Sequence Modification

European Commission

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History

Publication

Angewandte Chemie Internatioanl Edition, 2023, 62, e202305759

Publisher

Wiley and Sons Ltd

Other Funding information

This project has received funding from Science Foundation Ireland (12/RC/2275_P2), the Irish Research Council (IR?CLA/2022/3815), and the Novo Nordisk Foundation (NNF22OC0077099). R. E. F. de P. acknowledges funding from the Government of Ireland Postdoctoral Fellowship program (GOIPD/2021/909). We acknowledge funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 861381 (NATURE-ETN). F. W. acknowledges funding from the Swedish Cancer Foundation (201145 PjF) and the Swedish Child Cancer Foundation (PR2019-0037 and PR2022-0014). R. F. and D. T. acknowledge super?computing time at the SFI/Higher Education Authority Irish Center for High-End Computing (ICHEC). Open Access funding provided by IReL

Also affiliated with

  • Bernal Institute

Sustainable development goals

  • (4) Quality Education

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  • Physics

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