title: Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor.
abstract: Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: M
authors.initials: M
authors.lastname: Flinspach
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Piekarz
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fellows
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hagan
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gibbs
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Neff
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: J
authors.initials: J
authors.lastname: Freedman
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Eckert
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bonesteel
authors.affiliation: Peptides International, Louisville, KY 40299, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Pennington
authors.affiliation: University of California, San Diego, Department Anesthesiology and Pharmacology, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Eddinger
authors.affiliation: University of California, San Diego, Department Anesthesiology and Pharmacology, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Yaksh
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hunter
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Swanson
authors.affiliation: Janssen R&D, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Wickenden
mesh_terms: D000818:Animals; D002460:Cell Line; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D010146:Pain / Q000378:metabolism* / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000737:chemistry / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C470626:ProTx-II peptide; C486866:SCN9A protein, human; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers