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Here, we isolated and characterized two novel \u03c9-conotoxins, MoVIA and MoVIB from\n                    <jats:italic>Conus moncuri<\/jats:italic>\n                    , the first to be identified in vermivorous (worm-hunting) cone snails. MoVIA and MoVIB potently inhibited human Ca\n                    <jats:sub>v<\/jats:sub>\n                    2.2 in fluorimetric assays and rat Ca\n                    <jats:sub>v<\/jats:sub>\n                    2.2 in patch clamp studies, and both potently displaced radiolabeled \u03c9-conotoxin GVIA (\n                    <jats:sup>125<\/jats:sup>\n                    I-GVIA) from human SH-SY5Y cells and fish brain membranes (IC\n                    <jats:sub>50<\/jats:sub>\n                    2\u20139\u2009pM). Intriguingly, an arginine at position 13 in MoVIA and MoVIB replaced the functionally critical tyrosine found in piscivorous \u03c9-conotoxins. To investigate its role, we synthesized MoVIB-[R13Y] and MVIIA-[Y13R]. Interestingly, MVIIA-[Y13R] completely lost Ca\n                    <jats:sub>v<\/jats:sub>\n                    2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous \u03c9-conotoxins whereas tyrosine 13 is preferred in piscivorous \u03c9-conotoxins. MoVIB reversed pain behavior in a rat neuropathic pain model, confirming that vermivorous cone snails are a new source of analgesic \u03c9-conotoxins. Given vermivorous cone snails are ancestral to piscivorous species, our findings support the repurposing of defensive venom peptides in the evolution of piscivorous\n                    <jats:italic>Conidae<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-31245-4","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T04:53:36Z","timestamp":1535950416000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Novel analgesic \u03c9-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides"],"prefix":"10.1038","volume":"8","author":[{"given":"Silmara R.","family":"Sousa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"McArthur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Brust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca F.","family":"Bhola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Johan","family":"Rosengren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7137-1656","authenticated-orcid":false,"given":"Lotten","family":"Ragnarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Dutertre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Alewood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-609X","authenticated-orcid":false,"given":"Macdonald J.","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7030-2288","authenticated-orcid":false,"given":"David J.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,7]]},"reference":[{"key":"31245_CR1","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1074\/mcp.M112.021469","volume":"12","author":"S Dutertre","year":"2013","unstructured":"Dutertre, S. et al. Deep venomics reveals the mechanism for expanded peptide diversity in cone snail venom. Mol Cell Proteomics 12, 312\u2013329, https:\/\/doi.org\/10.1074\/mcp.M112.021469 (2013).","journal-title":"Mol Cell Proteomics"},{"key":"31245_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2755-6","volume":"17","author":"MA Phuong","year":"2016","unstructured":"Phuong, M. A., Mahardika, G. N. & Alfaro, M. E. Dietary breadth is positively correlated with venom complexity in cone snails. BMC Genomics 17, 401, https:\/\/doi.org\/10.1186\/s12864-016-2755-6 (2016).","journal-title":"BMC Genomics"},{"key":"31245_CR3","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1124\/pr.111.005322","volume":"64","author":"RJ Lewis","year":"2012","unstructured":"Lewis, R. J., Dutertre, S., Vetter, I. & Christie, M. J. Conus venom peptide pharmacology. 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