{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:32:43Z","timestamp":1789993963663,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T00:00:00Z","timestamp":1566432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["Pain-T and PEPTOPAIN"],"award-info":[{"award-number":["Pain-T and PEPTOPAIN"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["FRM 2015"],"award-info":[{"award-number":["FRM 2015"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1\u20131.3 and 1.5\u20131.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure\u2013activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates.<\/jats:p>","DOI":"10.3390\/toxins11090484","type":"journal-article","created":{"date-parts":[[2019,8,23]],"date-time":"2019-08-23T10:15:07Z","timestamp":1566555307000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates"],"prefix":"10.3390","volume":"11","author":[{"given":"T\u00e2nia C.","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"},{"name":"Sanofi R&amp;D, Integrated Drug Discovery\u2014High Content Biology, F-94440 Vitry-sur-Seine, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lesport","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle (IGF), CNRS-UMR 5203, Inserm-U661, Universit\u00e9 de Montpellier, Laboratories of Excellence\u2014Ion Channel Science and Therapeutics, F-34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kuylle","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Stura","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Ciolek","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Mourier","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0774-1691","authenticated-orcid":false,"given":"Denis","family":"Servent","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-0419","authenticated-orcid":false,"given":"Emmanuel","family":"Bourinet","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle (IGF), CNRS-UMR 5203, Inserm-U661, Universit\u00e9 de Montpellier, Laboratories of Excellence\u2014Ion Channel Science and Therapeutics, F-34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5501-0888","authenticated-orcid":false,"given":"Evelyne","family":"Benoit","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"},{"name":"Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR CNRS\/Universit\u00e9 Paris-Sud 9197, Universit\u00e9 Paris-Saclay, F-91198 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Gilles","sequence":"additional","affiliation":[{"name":"Service d\u2019Ing\u00e9nierie Mol\u00e9culaire des Prot\u00e9ines (SIMOPRO), CEA, Universit\u00e9 Paris-Saclay, F-91191 Gif sur Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Goldberg, D.S., and Mcgee, S.J. 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