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

The spider venom peptide Huwentoxin-IV (HwTx-IV) 1 is a potent antagonist of hNa(v)1.7 (IC50 determined herein as 17 +/- 2 nM). Na(v)1.7 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 Na(v)1.7 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 hNa(v)1.7 while maintaining the original selectivity profile of the wild-type peptide 1 on hNa(v)1.5. Peptide 47 (Glyl, Gly(4), Trp(33)-HwTx) demonstrated the largest potency increase on hNav1.7 (IC50 0.4 +/- 0.1 nM). (C) 2013 Elsevier Inc. All rights reserved.