Decoding the Sequence Determinants of DNA Cleavage in Histidine-Containing Copper(II) Metallopeptides
Year: 2026
Type: preprint
Abstract: The increasing global incidence of cancer, emerging viral infections, and antimicrobial resistance highlights the urgent need for innovative therapeutics with novel mechanisms of action. Nucleic acids, central to genetic information processing, are promising targets for therapeutic intervention through selective cleavage. Inspired by the biological activity of DNases and RNases, peptide-based metallonucleases—particularly those containing histidine—have emerged as versatile agents with tunable activity and potential applications in treating genetic diseases, including cancer. By analyzing a set of six copper(II) complexes with different histidine-containing tripeptides, this work investigates how peptide sequence influences several factors determining DNA-cleavage efficiency, such as speciation and conditional affinity at physiological pH, coordination mode, DNA binding, and ROS production. These findings offer a new framework for designing peptide-based copper nucleases and possibly identify a non-ATCUN sequence as a promising lead structure.
Source: ChemRxiv
Authors: Ana B. Caballero, Olga Iranzo, Patrick Gamez
Institutions: Institut de Nanociència i Nanotecnologia de la Universitat de Barcelona, Universitat de Barcelona, Centre National de la Recherche Scientifique, Aix-Marseille Université, Centrale Méditerranée, Institut des Sciences Moléculaires de Marseille, Institut de Biomedicina de la Universitat de Barcelona
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7220660446