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However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF\u2010melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin\u2010peptide from the <jats:italic><jats:styled-content style=\"fixed-case\">Octopus kaurna<\/jats:styled-content><\/jats:italic>, Octpep\u20101 in melanoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We evaluated the cytotoxicity of Octpep\u20101 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep\u20101 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR\/Cas9 technology, high\u2010throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Octpep\u20101 selectively reduced the proliferative capacity of human melanoma BRAF<jats:sup>V600E<\/jats:sup>\u2010mutated cells with minimal effects on fibroblasts. In melanoma\u2010treated cells, Octpep\u20101 increased ROS with unaltered mitochondrial membrane potential and promoted non\u2010mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep\u20101 depends upon the \u03b1\u2010helix and polyproline conformation in the C\u2010terminal region of the peptide. A truncated form of the C\u2010terminal end of Octpep\u20101 displayed enhanced potency and efficacy against melanoma. Octpep\u20101 reduced the progression of tumours in xenograft melanoma mice and zebrafish.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>We unravel the intrinsic anti\u2010tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF\u2010mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15923","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T09:56:41Z","timestamp":1657619801000},"page":"4878-4896","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The structural conformation of the tachykinin domain drives the anti\u2010tumoural activity of an octopus peptide in melanoma BRAF<sup>V600E<\/sup>"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-8554","authenticated-orcid":false,"given":"Javier","family":"Moral\u2010Sanz","sequence":"first","affiliation":[{"name":"Translational Venomics Group Madrid Institute for Advanced Studies in Food  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2240-1951","authenticated-orcid":false,"given":"Manuel A.","family":"Fernandez\u2010Rojo","sequence":"additional","affiliation":[{"name":"Hepatic Regenerative Medicine Group Madrid Institute for Advanced Studies in Food  Madrid Spain"},{"name":"Hepatic Fibrosis Group, Department of Cell and Molecular Biology QIMR Berghofer Medical Research Institute  Herston Queensland Australia"},{"name":"Diamantina Institute The University of Queensland  St. Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-4547","authenticated-orcid":false,"given":"Gonzalo","family":"Colmenarejo","sequence":"additional","affiliation":[{"name":"Biostatistics &amp; Bioinformatics Unit Madrid Institute for Advances Studies in Food  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Kurdyukov","sequence":"additional","affiliation":[{"name":"Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, and School of Life and Environmental Sciences University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Brust","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7137-1656","authenticated-orcid":false,"given":"Lotten","family":"Ragnarsson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa","family":"Andersson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabela F.","family":"Vila","sequence":"additional","affiliation":[{"name":"Translational Venomics Group Madrid Institute for Advanced Studies in Food  Madrid Spain"},{"name":"Department of Zoology, Genetics and Physical Anthropology University of Santiago de Compostela  Lugo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Cabezas\u2010Sainz","sequence":"additional","affiliation":[{"name":"Department of Zoology, Genetics and Physical Anthropology University of Santiago de Compostela  Lugo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5164-248X","authenticated-orcid":false,"given":"Patrick","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Vela\u2010Sebasti\u00e1n","sequence":"additional","affiliation":[{"name":"Translational Venomics Group Madrid Institute for Advanced Studies in Food  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Fern\u00e1ndez\u2010Carrasco","sequence":"additional","affiliation":[{"name":"Translational Venomics Group Madrid Institute for Advanced Studies in Food  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanni K. 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