Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption
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 de...
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Nature Portfolio
2021
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oai:doaj.org-article:6c1a2a9787704316b967c97b4adbe0f92021-12-02T17:23:49ZCopper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption10.1038/s41598-021-91670-w2045-2322https://doaj.org/article/6c1a2a9787704316b967c97b4adbe0f92021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91670-whttps://doaj.org/toc/2045-2322Abstract 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.Fatih ComertFrank HeinrichAnanda ChowdhuryMason SchoeneckCaitlin DarlingKyle W. AndersonM. Daben J. LibardoAlfredo M. Angeles-BozaVitalii SilinMyriam L. CottenMihaela MihailescuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021) |
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Medicine R Science Q |
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Medicine R Science Q Fatih Comert Frank Heinrich Ananda Chowdhury Mason Schoeneck Caitlin Darling Kyle W. Anderson M. Daben J. Libardo Alfredo M. Angeles-Boza Vitalii Silin Myriam L. Cotten Mihaela Mihailescu Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| description |
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. |
| format |
article |
| author |
Fatih Comert Frank Heinrich Ananda Chowdhury Mason Schoeneck Caitlin Darling Kyle W. Anderson M. Daben J. Libardo Alfredo M. Angeles-Boza Vitalii Silin Myriam L. Cotten Mihaela Mihailescu |
| author_facet |
Fatih Comert Frank Heinrich Ananda Chowdhury Mason Schoeneck Caitlin Darling Kyle W. Anderson M. Daben J. Libardo Alfredo M. Angeles-Boza Vitalii Silin Myriam L. Cotten Mihaela Mihailescu |
| author_sort |
Fatih Comert |
| title |
Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| title_short |
Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| title_full |
Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| title_fullStr |
Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| title_full_unstemmed |
Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| title_sort |
copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/6c1a2a9787704316b967c97b4adbe0f9 |
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