μ‐Conotoxin KIIIA peptidomimetics that block human voltage‐gated sodium channels,Peptide Science

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μ‐Conotoxin KIIIA peptidomimetics that block human voltage‐gated sodium channels
Peptide Science ( IF 1.5 ) Pub Date : 2020-10-24 , DOI: 10.1002/pep2.24203
Astrid Knuhtsen ₁ , Rachel Whiting ₂ , Fergus S. McWhinnie ₁ , Charlotte Whitmore ₂ , Brian O. Smith ₃ , A. Christopher Green ₂ , Christopher M. Timperley ₂ , Kenneth I. Kinnear ₂ , Andrew G. Jamieson ₁

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Peptidomimetics designed to target voltage‐gated sodium channels have attracted significant attention as potential analgesics. However, voltage‐gated sodium channel (VGSC)‐blocking activity of these compounds has mainly been assessed using rat and/or mice homologs. In this study, we developed a novel series of conformationally constrained peptidomimetic analogues of the μ‐conotoxin KIIIA and assessed their activity against human VGSCs. Two of the mimetics block the currents of hNa_v1.4 and hNa_v1.6 channels. NMR derived structures of the mimetics provided excellent insight into the structural requirements for bioactivity. A lactam‐constrained analogue, previously reported to be active in mice, did not block the corresponding human VGSC. This work highlights important differences in VGSCs between species and validates the potential of peptidomimetics as human analgesics.

中文翻译：

μ-芋螺毒素KIIIA拟肽可阻断人电压门控性钠通道

设计为靶向电压门控钠通道的拟肽作为潜在的止痛药引起了广泛的关注。但是，这些化合物的电压门控钠通道（VGSC）阻断活性主要是使用大鼠和/或小鼠同源物进行评估的。在这项研究中，我们开发了一系列新的μ-芋螺毒素KIIIA的构象约束肽模拟物，并评估了它们对人VGSC的活性。两种模拟物可阻断hNa _v 1.4和hNa _v的电流1.6个频道。模拟物的NMR衍生结构为生物活性的结构要求提供了出色的见解。以前据报道在小鼠中具有内酰胺约束的类似物没有激活相应的人VGSC。这项工作强调了物种之间VGSC的重要区别，并验证了拟肽作为人类止痛剂的潜力。

更新日期：2020-10-24

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