{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:35:18Z","timestamp":1791272118507,"version":"4.1.0"},"reference-count":62,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2015,3,4]],"date-time":"2015-03-04T00:00:00Z","timestamp":1425427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP110103129"],"award-info":[{"award-number":["DP110103129"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00NS073797"],"award-info":[{"award-number":["R00NS073797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1044414"],"award-info":[{"award-number":["APP1044414"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"Background and Purpose<\/jats:title>Chronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose\u2010limiting side effects. Humans with loss\u2010of\u2010function mutations in the voltage\u2010gated sodium channel NaV<\/jats:sub><\/jats:styled-content>1.7 (hNaV<\/jats:sub><\/jats:styled-content>1.7) are indifferent to pain, making hNaV<\/jats:sub><\/jats:styled-content>1.7 a promising target for analgesic development. Since spider venoms are replete with NaV<\/jats:sub> channel modulators, we examined their potential as a source of hNaV<\/jats:sub><\/jats:styled-content>1.7 inhibitors.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We developed a high\u2010throughput fluorescent\u2010based assay to screen spider venoms against hNaV<\/jats:sub><\/jats:styled-content>1.7 and isolate \u2018hit\u2019 peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S<\/jats:styled-content>3b\u2010S4 paddle motif from each voltage sensor domain of hNaV<\/jats:sub><\/jats:styled-content>1.7 was transplanted into the homotetrameric KV<\/jats:sub><\/jats:styled-content>2.1 channel.<\/jats:p><\/jats:sec>Key Results<\/jats:title>We screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV<\/jats:sub><\/jats:styled-content>1.7. By deconvoluting \u2018hit\u2019 venoms, we discovered seven novel members of the NaSpTx<\/jats:styled-content> family 1. One of these peptides, H<\/jats:styled-content>d1a (peptide \u03bc\u2010TRTX\u2010Hd1a from venom of the spider Haplopelma doriae<\/jats:italic>), inhibited hNaV<\/jats:sub><\/jats:styled-content>1.7 with a high level of selectivity over all other subtypes, except hNaV<\/jats:sub><\/jats:styled-content>1.1. We showed that H<\/jats:styled-content>d1a is a gating modifier that inhibits hNaV<\/jats:sub><\/jats:styled-content>1.7 by interacting with the S<\/jats:styled-content>3b\u2010S<\/jats:styled-content>4 paddle motif in channel domain II. The structure of H<\/jats:styled-content>d1a, determined using heteronuclear NMR<\/jats:styled-content>, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>Our data indicate that spider venoms are a rich natural source of hNaV<\/jats:sub><\/jats:styled-content>1.7 inhibitors that might be useful leads for the development of novel analgesics.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13081","type":"journal-article","created":{"date-parts":[[2015,3,4]],"date-time":"2015-03-04T11:43:04Z","timestamp":1425469384000},"page":"2445-2458","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Seven novel modulators of the analgesic target NaV<\/sub><\/scp>1.7 uncovered using a high\u2010throughput venom\u2010based discovery approach"],"prefix":"10.1111","volume":"172","author":[{"given":"Julie K","family":"Klint","sequence":"first","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J","family":"Smith","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darshani B","family":"Rupasinghe","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sing Yan","family":"Er","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Senff","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Herzig","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Mobli","sequence":"additional","affiliation":[{"name":"Centre for Advanced Imaging The University of Queensland St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J","family":"Lewis","sequence":"additional","affiliation":[{"name":"Centre for Pain Research Institute for Molecular Bioscience St. Lucia Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Bosmans","sequence":"additional","affiliation":[{"name":"Department of Physiology Johns Hopkins University Baltimore MD USA"},{"name":"Solomon H. 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