具有镇痛活性的基于肽的钠通道阻滞剂μ-芋螺毒素的结构与功能
Structure and function of μ-conotoxins, peptide-based sodium channel blockers with analgesic activity.
作者信息
Green Brad R, Bulaj Grzegorz, Norton Raymond S
机构信息
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
出版信息
Future Med Chem. 2014 Oct;6(15):1677-98. doi: 10.4155/fmc.14.107.
Abstract
μ-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified µ-conotoxins that preferentially blocked the skeletal muscle subtype (NaV1.4). However, the last decade witnessed a significant increase in the number of µ-conotoxins and the range of VGSC subtypes inhibited (NaV1.2, NaV1.3 or NaV1.7). Twenty µ-conotoxin sequences have been identified to date and structure-activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of µ-conotoxins, which show promise for development of selective blockers of NaV1.2, and perhaps also NaV1.1,1.3 or 1.7.
摘要
μ-芋螺毒素可阻断电压门控钠通道（VGSCs），并与河豚毒素竞争结合钠电导孔。早期研究发现了优先阻断骨骼肌亚型（NaV1.4）的μ-芋螺毒素。然而，在过去十年中，μ-芋螺毒素的数量显著增加，其抑制的VGSC亚型范围也有所扩大（NaV1.2、NaV1.3或NaV1.7）。迄今为止，已鉴定出20种μ-芋螺毒素序列，对其中几种的构效关系研究确定了与VGSC亚型相互作用的关键残基。体内镇痛和神经肌肉阻断活性推动了亚型特异性工程化的研究。本综述总结了μ-芋螺毒素的结构和药理学研究，这些研究显示出开发NaV1.2以及可能还有NaV1.1、1.3或1.7选择性阻滞剂的前景。
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