Expanding the DNA damaging potential of artificial metallo-nucleases with click chemistry
Recently, copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) click chemistry has emerged as a promising approach for designing new artificial metallo-nucleases (AMNs) with DNA-damaging properties. By functionalising a central organic azide with three alkyne donors, Tri-Click (TC) ligands capable of chelating three copper ions through the donor group and triazole linker can be generated. However, the versatility of this approach along with the influence of specific donors on metal binding, DNA recognition, and cellular DNA damage in an anticancer context remains poorly understood. Here, we prepare a series of Tri-Click ligands incorporating systematic cyclic and acyclic N-, O-, and S-donors and evaluate their AMN activities. Screening experiments pinpoint planar N-donor ligands as high value agents. Among these, the copper complex of Tri-Click-Pyridine (Cu<sub>3</sub>-TC-Py) displays significant potential. We characterise its activity using single-molecule imaging, microscale thermophoresis, FRET-based binding assays, molecular dynamics, and intracellular DNA interaction studies in human and functional bacterial cells. We report the emergence of Cu<sub>3</sub>-TC-Py as a lead AMN with high reactivity for DNA damage applications central to anticancer therapy.
Authors
- Pegah Johansson (ORCID: https://orcid.org/0000-0002-0376-0617)
- Sriram KK (ORCID: https://orcid.org/0000-0002-4661-242X)
- Francisca Figueiredo (ORCID: https://orcid.org/0009-0003-1187-7684)
- Kevin Cariou
- Michaela Wenzel (ORCID: https://orcid.org/0000-0001-9969-6113)
- Margareth Sidarta (ORCID: https://orcid.org/0000-0002-8812-4782)
- Shayon Bhattacharya (ORCID: https://orcid.org/0000-0002-4218-0308)
- Obed Akwasi Aning (ORCID: https://orcid.org/0000-0002-4002-2787)
- Fredrik Westerlund (ORCID: https://orcid.org/0000-0002-4767-4868)
- Pierre Mesdom (ORCID: https://orcid.org/0000-0003-1069-2138)
- Vickie McKee
- Alex Gibney
- Lily Arrué
- Andrew Kellett
- Hedvig Hjerpe
- Eva Delahunt
- Gilles Gasser
- Damien Thompson
Institutions
- Centre National de la Recherche Scientifique (FR)
- Chimie ParisTech - PSL (FR)
- University of Southern Denmark (DK)
- University of Limerick (IE)
- Université Paris Sciences et Lettres (FR)
- Sahlgrenska University Hospital (SE)
- Region Västra Götaland (SE)
- Dublin City University (IE)
- Chalmers University of Technology (SE)
- University of Gothenburg (SE)
- University of Jyväskylä (FI)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-03
- DOI
- https://doi.org/10.1038/s41467-026-68911-5
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Swedish Cancer Foundation
- European Commission
- Agence Nationale de la Recherche
- Irish Research Council
- Novo Nordisk
- Vetenskapsrådet
- Novo Nordisk Fonden
- Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer