Expanding the DNA damaging potential of artificial metallo-nucleases with click chemistry
Journal article, 2026
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 (Cu3-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 Cu3-TC-Py as a lead AMN with high reactivity for DNA damage applications central to anticancer therapy.
Author
Alex Gibney
Dublin City University
Margareth Sidarta
Molecular Bioscience
Eva Delahunt
Dublin City University
Pierre Mesdom
Université Paris PSL
Lily Arrue
University of Jyväskylä
University of Limerick
Obed Akwasi Aning
Chalmers, Life Sciences, Chemical Biology
Hedvig Hjerpe
University of Gothenburg
Francisca Figueiredo
Université Paris PSL
Kevin Cariou
Université Paris PSL
Vickie McKee
Dublin City University
University of Southern Denmark
Pegah Johansson
University of Gothenburg
Shayon Bhattacharya
University of Limerick
Damien Thompson
University of Limerick
Michaela Wenzel
Molecular Bioscience
Gilles Gasser
Université Paris PSL
Fredrik Westerlund
Molecular Bioscience
Andrew Kellett
Dublin City University
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 17 1 2309Next Generation Nanofluidic Devices for Single Molecule Analysis of DNA Repair Dynamics
European Commission (EC) (EC/H2020/866238), 2020-04-01 -- 2025-03-31.
Real-Time Visualization of DNA Repair - One Molecule at a Time
Swedish Research Council (VR) (2020-03400), 2021-01-01 -- 2024-12-31.
Detecting antibiotic-induced DNA damage in bacteria by single-molecule DNA microscopy
AoA Health Engineering, 2022-09-01 -- 2023-12-31.
AoA Nanoscience and Nanotechnology, 2023-08-01 -- 2023-12-31.
Subject Categories (SSIF 2025)
Molecular Biology
Basic Medicine
Cell Biology
Microbiology
Inorganic Chemistry
Organic Chemistry
Medicinal Chemistry
Biochemistry
Physical Chemistry
Areas of Advance
Nanoscience and Nanotechnology
Health Engineering
Roots
Basic sciences
Infrastructure
Myfab (incl. Nanofabrication Laboratory)
DOI
10.1038/s41467-026-68911-5
PubMed
41634027
Related datasets
Expanding the DNA Damaging Potential of Artificial Metallo-Nucleases with Click Chemistry [dataset]
URI: https://zenodo.org/records/17143195