Year: 2026
Type: article
Abstract: 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 3 -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 3 -TC-Py as a lead AMN with high reactivity for DNA damage applications central to anticancer therapy.
Source: Nature Communications
Institutions: Dublin City University, Chalmers University of Technology, University of Gothenburg, Centre National de la Recherche Scientifique, Chimie ParisTech - PSL, Université Paris Sciences et Lettres, Institute of Chemistry for Life and Health Sciences, University of Limerick, University of Jyväskylä, Sahlgrenska University Hospital, University of Southern Denmark
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Swedish Cancer Foundation, European Commission, Science Foundation Ireland, Agence Nationale de la Recherche, Svenska Forskningsrådet Formas, Irish Research Council, Novo Nordisk, Vetenskapsrådet, Novo Nordisk Fonden, Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer, Horizon 2020 Framework Programme, H2020 European Research Council
Awards: G1379612634, G1556356419, G2137956802, Paris Sciences et Lettres, G3543229056, Catalysis in Cells using Light and Supramolecular Metallic Scaffolds, G3953683450, G4190806336, G4292778654, G434337789, Nucleic Acids for Future Gene Editing, Immunotherapy and Epigenetic Sequence Modification, G4676508853, G471331628, G4807309799, Real-Time Visualization of DNA Repair - One Molecule at a Time, G6759105742, G6890356334, G69740266, G7117850829, G7240651115, G7367701772, G7724219939, SSPC_Phase 2, G782245399, Next Generation Nanofluidic Devices for Single Molecule Analysis of DNA Repair Dynamics, G8176586574
OpenAlex ID: W7127278741