Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption

Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption Fatih Comert, Frank Heinrich, Ananda Chowdhury, Mason Schoeneck, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-228006/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version 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 is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that the metallated 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 is particularly effective at inserting its metallated motif in bilayers, causing water crevices in the hydrocarbon region and placing Cu 2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where metallating HDPs to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics. Chemical Biology Biophysics Structural Biology Antimicrobial Peptides Anticancer Peptides Host Defense Peptides Reactive Oxygen Species Copper Neutron Diffraction Surface Plasmon Resonance Electrical Impedance Spectroscopy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations No competing interests reported. Supplementary Files SINRP1P3Cu9Feb2021FormattedFINAL.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 29 Apr, 2021 Reviews received at journal 06 Apr, 2021 Reviewers agreed at journal 06 Apr, 2021 Reviewers invited by journal 22 Mar, 2021 Editor assigned by journal 16 Mar, 2021 Editor invited by journal 11 Mar, 2021 Submission checks completed at journal 02 Mar, 2021 First submitted to journal 09 Feb, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-228006","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":14408968,"identity":"38cf3cfc-c0de-4f1f-9336-b185fa4eeedd","order_by":0,"name":"Fatih Comert","email":"","orcid":"","institution":"Institute for Bioscience and Biotechnology Research, Rockville, MD 20850","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fatih","middleName":"","lastName":"Comert","suffix":""},{"id":14408969,"identity":"12202e38-cdaa-4928-a9e5-855cf3307ecc","order_by":1,"name":"Frank Heinrich","email":"","orcid":"","institution":"Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Heinrich","suffix":""},{"id":14408970,"identity":"1059e7d2-023b-43d1-9250-becaa9f8b4ec","order_by":2,"name":"Ananda Chowdhury","email":"","orcid":"","institution":"Institute for Bioscience and Biotechnology Research, Rockville, MD 20850","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ananda","middleName":"","lastName":"Chowdhury","suffix":""},{"id":14408971,"identity":"cde96825-5296-4027-8be3-58aa276f4291","order_by":3,"name":"Mason Schoeneck","email":"","orcid":"","institution":"University of Rochester School of Medicine and Dentistry, Rochester, NY 14620","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mason","middleName":"","lastName":"Schoeneck","suffix":""},{"id":14408972,"identity":"92e1188b-7285-4c7e-86f4-93d9e253c521","order_by":4,"name":"Caitlin Darling","email":"","orcid":"","institution":"Department of Biological Sciences, Clemson University, Clemson, SC 29634","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Caitlin","middleName":"","lastName":"Darling","suffix":""},{"id":14408973,"identity":"7c3ca543-8061-4803-afda-c4320da4b591","order_by":5,"name":"Kyle W. Anderson","email":"","orcid":"","institution":"Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD 20899","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kyle","middleName":"W.","lastName":"Anderson","suffix":""},{"id":14408974,"identity":"5abace95-a1ad-4277-a173-1df132f89c85","order_by":6,"name":"M. Daben J. Libardo","email":"","orcid":"","institution":"Department of Chemistry and Institute of Materials Science, University of Connecticut, Storrs, CT 06269","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"M.","middleName":"Daben J.","lastName":"Libardo","suffix":""},{"id":14408975,"identity":"065c3d12-6430-4b27-8a9e-5a0e58d329e1","order_by":7,"name":"Alfredo M. Angeles-Boza","email":"","orcid":"","institution":"Department of Chemistry and Institute of Materials Science, University of Connecticut, Storrs, CT 06269","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alfredo","middleName":"M.","lastName":"Angeles-Boza","suffix":""},{"id":14408976,"identity":"131781f6-41fa-46b6-a399-ac20fecd5ea0","order_by":8,"name":"Vitalii Silin","email":"","orcid":"","institution":"Institute for Bioscience and Biotechnology Research, Rockville, MD 20850","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vitalii","middleName":"","lastName":"Silin","suffix":""},{"id":14408977,"identity":"df46ce32-7569-48ac-b63b-db037b7343e6","order_by":9,"name":"Myriam L. Cotten","email":"","orcid":"","institution":"Department of Applied Science, William and Mary, Williamsburg, VA 23185","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Myriam","middleName":"L.","lastName":"Cotten","suffix":""},{"id":14408978,"identity":"9c1d2687-d4fa-4b47-a28c-2763eebbd7bc","order_by":10,"name":"Mihaela Mihailescu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYFACxjYGBgMLMOtBYsMBsJgEAwMzIS0SIBazAZFaGNggaoAMCUZitPCLHW578KNAQk6+/YxZxcMdd/IZJLITbzBUWCc24NAiOTux3bDHQMLY4EyO2Y3EM88sGyRyN1swnEnHqcXgdmKbBI+BROIGCR6glrbDBgwSudskGNsO49RiD9Qi+cdAon7+DB6zAoSWf7i1GEgntkkDbUlguMFjxoDQ0oBbiwTQFmkZAwnDDWfSiiWAfjFg43m72SLhWLoxLi38s9OfSb75YyMv335448efO+4Y8LPnbrzxocZaFpcWTACKJoYEopWPglEwCkbBKMAGAME6V+7JH6vSAAAAAElFTkSuQmCC","orcid":"","institution":"Institute for Bioscience and Biotechnology Research, Rockville, MD 20850","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mihaela","middleName":"","lastName":"Mihailescu","suffix":""}],"badges":[],"createdAt":"2021-02-09 19:59:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-228006/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-228006/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6565751,"identity":"9e45b75d-7c9b-4f3e-8e24-bf37276d37c6","added_by":"auto","created_at":"2021-03-03 15:14:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":179318,"visible":true,"origin":"","legend":"Cytotoxicity Assays for the Apo- and Holo-states of P1 and P3 Acting on Cancer Cells. Fibrosarcoma (HT1080), breast (MDA-MB-231), and lung (A549) cancer cell lines (panels A, B, and C, respectively) were used to measure cell viability after 24 h of treatment with different concentrations (M = mol/L) of P1 and P3 in the apo- and Cu2+-bound states. Error bars are standard deviations based on triplicates. The IC50 values are summarized in Table 1. Similar results were obtained after 48 h (Fig. S1). The peptides were metallated using a 1:1 stoichiometric amount of CuCl2. Panel C: MD-MBA-231 cells exposed to 100 nM MitoTracker (red), 5 ug/mL Hoescht 33258, and 4 umol/L FITC-labeled P1 or P3 (green) for 20 mins. Top row: FITC-P1 stains the cellular membrane and nuclear envelope and co-localizes with MitoTracker. Bottom row: FITC-P3 stains the cellular membrane and there is co-localization with MitoTracker (left cell). Scale bar represents 5 um.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/dd9d17577d7156d65b3a60ac.jpg"},{"id":6565128,"identity":"8a16c14d-0a74-4c89-881b-fb70dcda73b1","added_by":"auto","created_at":"2021-03-03 15:11:20","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":151002,"visible":true,"origin":"","legend":"Techniques for Investigating Peptide-bilayer Structural Interactions. (A) High-resolution structure of piscidin P1: FFHHIFRGIVHVGKTIHRLVTG (MW 2,571) and (B) Piscidin P3: FIHHIFRGIVHAGRSIGRFLTG (MW, 2,492). The shown structures were determined by solid state NMR in 4:1 POPC/cholesterol bilayers at P/L = 1:4058. The corresponding Protein Data Bank IDs are 6PF0 (P1) and 6PEZ (P3). The u-helices of the peptides lay at the bilayer-water interface, adopting orientations that are almost parallel to the bilayer surface. (C) Cartoon describing the tethered bilayer membrane used for Surface Plasmon Resonance (SPR), Electrical Impedance Spectroscopy (EIS) and neutron reflectometry (NR). The tethered molecules (green) create a 10 Å thick sub-membrane aqueous space. (D) The simplest electric circuit model to describe the surface-supported bilayer, characterized by the membrane capacitance (Cm), resistance (Rm) and solvent resistance (Rsol). (E) Oriented lipid multilayers with peptide incorporated as described in the Methods for the neutron diffraction (ND) experiments. The repeat spacing (d) denotes the dimension of the repeat unit (thickness of the bilayer with its hydration layer).","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/f636af5f0e9bdd78ac76b2fc.jpg"},{"id":6565750,"identity":"cb5f389e-4461-4517-80b4-a1b3cf08f178","added_by":"auto","created_at":"2021-03-03 15:14:21","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":240062,"visible":true,"origin":"","legend":"SPR/EIS of P1 and P3 with or without Cu2+. The black curves are the SPR responses, and the blue curves are the calculated bilayer resistances from EIS measurements. Peptides were added in small increments on top of a stable POPC tBLM. SPR/EIS signals were collected simultaneously as a function of time: (A) P1, (B) P3, (C) P1-Cu2+, and (D) P3-Cu2+. The peptides were metallated using a 1:1 stoichiometric amount of CuCl2. See also Fig. S3. (uM = umol/L).","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/ac4d767792c8d88c9c4a65ea.jpg"},{"id":6565752,"identity":"9ecb23b0-eb06-402c-98cd-fb5fb322bce8","added_by":"auto","created_at":"2021-03-03 15:14:21","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":111590,"visible":true,"origin":"","legend":"Neutron Reflectometry of P1 and P3 in the Apo- and Holo-states. The time and ensemble average spatial profiles of the various components of the tBLM (Fig. 2 A) are shown as projections on the normal to the bilayer surface for (A) P1, (B) P3, (C) P1-Cu2+, and (D) P3- Cu2+. The peptides were metallated using a 1:1 stoichiometric amount of CuCl2. The inner bilayer leaflet is attached to the gold coated substrate (yellow) via molecular tethers (green). The outer leaflet of the bilayer is exposed to the aqueous compartment from which each peptide solution is injected.","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/ce4924c49ed1e522efab3e0c.jpg"},{"id":6565749,"identity":"fcef3650-5360-4c1a-9b5d-a8dbe0e852cc","added_by":"auto","created_at":"2021-03-03 15:14:21","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":142269,"visible":true,"origin":"","legend":"Bilayer Scattering Length Density Profiles from Neutron Diffraction on Oriented Lipid Multilayers. (A) The scattering length density (SLD) profiles of the bilayer are shown as projections on the bilayer normal (z-axis) for POPC (black), P1/POPC (dark red), and P1-Cu2+/POPC (pink). The peptides were metallated using a 1:1 stoichiometric amount of CuCl2. The corresponding water profiles, determined from H2O/2H2O contrast are overlaid for POPC (black), P1/POPC (dark blue), and P1-Cu2+/POPC (light blue). Peptides distribute equally on both sides of the bilayer during their incubation with liposomes and deposition on the substrate (see Methods). (B) Same as in (A) but for P3. All oriented samples were prepared in POPC at P/L = 1:25, and measured at 23 OC and 93% relative humidity achieved by using the vapor phase of saturated salt solutions. The small error bars on the curves represent the uncertainty in the profiles, which were calculated using a 95% confidence interval in the Monte-Carlo sampling of the structure factors 86. Structure factors and standard deviations are given in Table S2. All profiles were determined on a perlipid scale using structure factors calibrated to reflect the composition of the unit cell and without explicitly determining the area per lipid.86","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/1aee67d297363fbba0eebbb7.jpg"},{"id":6565748,"identity":"57a52121-866d-49b7-b62b-bf167965b7bc","added_by":"auto","created_at":"2021-03-03 15:14:20","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":81848,"visible":true,"origin":"","legend":"Positioning of P3-Cu2+ in the Bilayer with ND and Deuterium Contrast. The SLD profiles of two groups of specifically deuterated amino acids near the N-terminus (I5d10F6d5; yellow) and C-terminus (F19d5L20d10; blue) of P3 were obtained, as well as their sum (red) (Methods). Each profile represents time and ensemble averages of each of deuterated groups in the thermally disordered bilayer. The overall profiles for the neat POPC bilayer with P3-Cu2+ (black) and the water distribution (blue) are overlaid on those for the deuterated groups. Measurements were done at P/L = 1:25, 23 oC, and 93% relative humidity. Uncertainty bands in the deuterium profiles (colored bands) were determined using a 68% confidence interval in the Monte-Carlo sampling of the measured structure factors86. The inset show representative average conformation of the P3 u-helix in the bilayer, using a 3D structure derived from the NMR structure (PDB ID # 6PEZ)58 and the predicted structure of the Cu2+-bound ATCUN motif based on density functional theory calculations64. The orientation of the α-helix in the bilayer is derived from the diffraction SLD profiles. The two deuterated sites are shown with yellow and blue; the Cu2+ ion (green sphere) is shown at a larger than true scale for better visibility.","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/22a8d12644dbea199b46aa21.jpg"},{"id":6565753,"identity":"1a03f8a7-6b94-4387-82c1-2121ecc25cbc","added_by":"auto","created_at":"2021-03-03 15:14:21","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":89987,"visible":true,"origin":"","legend":"Absorbance Measurements in Polyunsaturated Lipid in the Presence of Cu2+. SUVs made of 3:1 DLPC/POPG were prepared and exposed to different forms and amounts of Cu2+: (A) Cu2+/L = 1:2 molar ratio (black), Cu2+/L=1:8 (red), Cu2+/L= 1:32 (blue), BHT/L=1:100, and Cu2+/L=1:8 (cyan) and lipid alone (magenta). (B) P1-Cu2+ (blue, dashed); P3- Cu2+ (red, dashed); P1 (blue); P3 (red); lipid alone (black). SUVs with peptides were prepared at P/L = 1:10. The source of free Cu2+ (CuCl2) was the same as that used for metallating P1 and P3. Measurements were taken in triplicates at 24 h after exposure. Uncertainties are smaller than line thicknesses.","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/5ef931be8fba63405a1839ab.jpg"},{"id":13599061,"identity":"4dc83885-a0ef-4a6b-9503-735307738405","added_by":"auto","created_at":"2021-09-17 05:38:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1791131,"visible":true,"origin":"","legend":"","description":"","filename":"PaperNRP1P3Cu9Feb2021FormattedFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1_covered.pdf"},{"id":6566361,"identity":"4b58c442-22d9-42a3-bcb2-33b29783f22f","added_by":"auto","created_at":"2021-03-03 15:17:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1805104,"visible":true,"origin":"","legend":"","description":"","filename":"PaperNRP1P3Cu9Feb2021FormattedFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1_stamped.pdf"},{"id":6565134,"identity":"57129b48-c2ac-4674-8780-cba50779ba50","added_by":"auto","created_at":"2021-03-03 15:11:21","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1324325,"visible":true,"origin":"","legend":"","description":"","filename":"SINRP1P3Cu9Feb2021FormattedFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-228006/v1/53c00b5339ebd45890875a97.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-228006/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antimicrobial Peptides, Anticancer Peptides, Host Defense Peptides, Reactive Oxygen Species, Copper, Neutron Diffraction, Surface Plasmon Resonance, Electrical Impedance Spectroscopy","lastPublishedDoi":"10.21203/rs.3.rs-228006/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-228006/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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 is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that the metallated 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 is particularly effective at inserting its metallated motif in bilayers, causing water crevices in the hydrocarbon region and placing Cu 2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where metallating HDPs to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.","manuscriptTitle":"Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-03 15:11:19","doi":"10.21203/rs.3.rs-228006/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-04-29T06:42:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-06T17:15:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206b345d-9fe4-41d5-83d1-f37d9ef61e12","date":"2021-04-06T11:34:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-03-22T07:20:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-03-16T14:03:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-03-11T05:18:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-03-02T11:55:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2021-02-09T19:51:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af1a43c8-e123-4a84-b4d8-6dea34ec6bcb","owner":[],"postedDate":"March 3rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":2741559,"name":"Chemical Biology"},{"id":2741560,"name":"Biophysics"},{"id":2741561,"name":"Structural Biology"}],"tags":[],"updatedAt":"2021-05-21T11:59:10+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-03 15:11:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-228006","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-228006","identity":"rs-228006","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}