MedImmune, Cambridge, United Kingdom.
Peptides. 2013 Jun;44:40-6. doi: 10.1016/j.peptides.2013.03.011. Epub 2013 Mar 19.
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).
蜘蛛毒液肽 Huwentoxin-IV（HwTx-IV）1 是 hNav1.7 的有效拮抗剂（本文中 IC50 值为 17 ± 2 nM）。Nav1.7 是一种电压门控钠离子通道，参与神经性和伤害性疼痛信号的产生和传导。我们制备了一些 HwTx-IV 类似物，作为 Nav1.7 拮抗作用的结构功能研究的一部分。这些类似物的抑制效力通过自动电生理学测定，并在本文中报告。特别是，天然残基 Glu(1)、Glu(4)、Phe(6)和 Tyr(33)被揭示为重要的活性调节剂，几个在这些位置发生突变的肽在 hNav1.7 上显示出显著增加的效力，同时保持野生型肽 1 对 hNav1.5 的原始选择性特征。肽 47（Gly(1)、Gly(4)、Trp(33)-HwTx）在 hNav1.7 上显示出最大的效力增加（IC50 0.4 ± 0.1 nM）。
