title: Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena.
abstract: The spider venom peptide Huwentoxin-IV (HwTx-IV) 1 is a potent antagonist of hNav1.7 (IC50 determined herein as 17 ± 2 nM). Nav1.7 is a voltage-gated sodium channel involved in the generation and conduction of neuropathic and nociceptive pain signals. We prepared a number of HwTx-IV analogs as part of a structure-function study into Nav1.7 antagonism. The inhibitory potency of these analogs was determined by automated electrophysiology and is reported herein. In particular, the native residues Glu(1), Glu(4), Phe(6) and Tyr(33) were revealed as important activity modulators and several peptides bearing mutations in these positions showed significantly increased potency on hNav1.7 while maintaining the original selectivity profile of the wild-type peptide 1 on hNav1.5. Peptide 47 (Gly(1), Gly(4), Trp(33)-HwTx) demonstrated the largest potency increase on hNav1.7 (IC50 0.4 ± 0.1 nM).
authors.affiliation: MedImmune, Cambridge, United Kingdom. revellj@medimmune.com
authors.forename: Jefferson D
authors.initials: JD
authors.lastname: Revell
authors.forename: Per-Eric
authors.initials: PE
authors.lastname: Lund
authors.forename: John E
authors.initials: JE
authors.lastname: Linley
authors.forename: Jacky
authors.initials: J
authors.lastname: Metcalfe
authors.forename: Nicole
authors.initials: N
authors.lastname: Burmeister
authors.forename: Sudharsan
authors.initials: S
authors.lastname: Sridharan
authors.forename: Clare
authors.initials: C
authors.lastname: Jones
authors.forename: Lutz
authors.initials: L
authors.lastname: Jermutus
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bednarek
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013111:Spider Venoms / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013112:Spiders; D013329:Structure-Activity Relationship; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers; C470632:huwentoxin IV, Selenocosmia huwena