Expanding the DNA damaging potential of artificial metallo-nucleases with click chemistry
Artikel i vetenskaplig tidskrift, 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.
Författare
Alex Gibney
Dublin City University
Margareth Sidarta
Molekylär biovetenskap
Eva Delahunt
Dublin City University
Pierre Mesdom
Université de recherche Paris Sciences et Lettres
Lily Arrue
Jyväskylän Yliopisto
University of Limerick
Obed Akwasi Aning
Chalmers, Life sciences, Kemisk biologi
Hedvig Hjerpe
Göteborgs universitet
Francisca Figueiredo
Université de recherche Paris Sciences et Lettres
Kevin Cariou
Université de recherche Paris Sciences et Lettres
Vickie McKee
Dublin City University
Syddansk Universitet
Pegah Johansson
Göteborgs universitet
Shayon Bhattacharya
University of Limerick
Damien Thompson
University of Limerick
Michaela Wenzel
Molekylär biovetenskap
Gilles Gasser
Université de recherche Paris Sciences et Lettres
Fredrik Westerlund
Molekylär biovetenskap
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
Europeiska kommissionen (EU) (EC/H2020/866238), 2020-04-01 -- 2025-03-31.
Visualisering av DNA-Reparation - En Molekyl i Taget
Vetenskapsrådet (VR) (2020-03400), 2021-01-01 -- 2024-12-31.
Single Molecule Imaging för att upptäcka DNA-skador i bakterier orsakas av antibiotika
Hälsa och teknik, 2022-09-01 -- 2023-12-31.
AoA Nanoscience and Nanotechnology, 2023-08-01 -- 2023-12-31.
Ämneskategorier (SSIF 2025)
Molekylärbiologi
Medicinska och farmaceutiska grundvetenskaper
Cellbiologi
Mikrobiologi
Oorganisk kemi
Organisk kemi
Läkemedelskemi
Biokemi
Fysikalisk kemi
Styrkeområden
Nanovetenskap och nanoteknik
Hälsa och teknik
Fundament
Grundläggande vetenskaper
Infrastruktur
Myfab (inkl. Nanotekniklaboratoriet)
DOI
10.1038/s41467-026-68911-5
PubMed
41634027
Relaterade dataset
Expanding the DNA Damaging Potential of Artificial Metallo-Nucleases with Click Chemistry [dataset]
URI: https://zenodo.org/records/17143195