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Copper‑binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption



Fatih Comert, Frank N. Heinrich, Ananda Chowdhury, Mason Schoeneck, Caitlin Darling, Kyle Anderson, M. Daben J. Libardo, Alfredo Angeles‑Boza, Vitalii I. Silin, Myriam Cotten, Mihaela Mihailescu


In the search for novel broad‑spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically‑active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs with Cu2+ is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that prepared as Cu2+‑complexes, the peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine‑rich, membrane‑interacting, and cell‑penetrating HDPs that are α‑helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid‑oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1‑apo is more potent than P3‑apo, metallation boosts their cytotoxicities by up to two‑ and seven‑fold, respectively. Remarkably, P3‑Cu2+ is particularly effective at inserting in bilayers, causing water crevices in the hydrocarbon region and placing Cu2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where complexing HDPs with Cu2+ to expand their mechanistic reach could be explored to design more potent peptide‑based anticancer therapeutics.


Comert, F. , Heinrich, F. , Chowdhury, A. , Schoeneck, M. , Darling, C. , Anderson, K. , Libardo, M. , Angeles‑Boza, A. , Silin, V. , Cotten, M. and Mihailescu, M. (2021), Copper‑binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption, Chemphyschem, [online],, (Accessed June 18, 2024)


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Created June 16, 2021, Updated October 18, 2022