Abstract
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.
Highlights
In the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest
In previous biophysical studies of piscidins 1 and 3 (P1/3), we demonstrated that the stronger membrane permeabilizing effects and pH-resiliency of piscidin 1 (P1) correlate with its higher histidine content and a membrane-inserted state that places its C-terminus in the bilayer c ore[56]
Free C u2+ tested at up to 30 μmol/L was not cytotoxic under the same conditions (Fig. S1B). While it is not known whether the peptides remain bound to Cu2+ throughout the process of killing cancer cells, it is essential for C u2+ and the peptides to be bound to each other in order to reach low IC50 values
Summary
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. Given the intersection between life-threatening infections and cancers, there is a strong motivation to develop therapeutics with broad-spectrum activity to treat both conditions simultaneously With this regard, several membrane-interacting host-defense peptides (HDPs) with cytotoxic properties against cancer cells have emerged as promising templates[7,8,15,16,17,18,19,20,21,22]. We show that these biological effects correlate with the ability of the peptides to physically and chemically impair lipid membranes
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