Referenced in: none

Automatically associated channels: Kir6.2 , Nav1.5 , Nav1.7 , TRP

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.

Authors: Jefferson D Revell, Per-Eric Lund, John E Linley, Jacky Metcalfe, Nicole Burmeister, Sudharsan Sridharan, Clare Jones, Lutz Jermutus, Maria A Bednarek

Journal, date & volume: Peptides, 2013 Jun , 44, 40-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23523779

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).