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从毒液中发现一种具有强效镇痛功效的新型Na1.7抑制剂。

Discovery of a Novel Na1.7 Inhibitor From Venom With Potent Analgesic Efficacy.

作者信息

Zhang Yunxiao, Peng Dezheng, Huang Biao, Yang Qiuchu, Zhang Qingfeng, Chen Minzhi, Rong Mingqiang, Liu Zhonghua

机构信息

The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.

出版信息

Front Pharmacol. 2018 Oct 16;9:1158. doi: 10.3389/fphar.2018.01158. eCollection 2018.

DOI:10.3389/fphar.2018.01158
PMID:30386239
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6198068/
Abstract

Spider venoms contain a vast array of bioactive peptides targeting ion channels. A large number of peptides have high potency and selectivity toward sodium channels. Na1.7 contributes to action potential generation and propagation and participates in pain signaling pathway. In this study, we describe the identification of μ-TRTX-Ca2a (Ca2a), a novel 35-residue peptide from the venom of Vietnam spider () that potently inhibits Na1.7 (IC = 98.1 ± 3.3 nM) with high selectivity against skeletal muscle isoform Na1.4 (IC > 10 μM) and cardiac muscle isoform Na1.5 (IC > 10 μM). Ca2a did not significantly alter the voltage-dependent activation or fast inactivation of Na1.7, but it hyperpolarized the slow inactivation. Site-directed mutagenesis analysis indicated that Ca2a bound with Na1.7 at the extracellular S3-S4 linker of domain II. Meanwhile, Ca2a dose-dependently attenuated pain behaviors in rodent models of formalin-induced paw licking, hot plate test, and acetic acid-induced writhing. This study indicates that Ca2a is a potential lead molecule for drug development of novel analgesics.

摘要

蜘蛛毒液含有大量靶向离子通道的生物活性肽。许多肽对钠通道具有高效力和选择性。Na1.7 有助于动作电位的产生和传播，并参与疼痛信号通路。在本研究中，我们描述了 μ-TRTX-Ca2a（Ca2a）的鉴定，它是一种来自越南蜘蛛（）毒液的新型 35 个氨基酸残基的肽，能有效抑制 Na1.7（IC = 98.1 ± 3.3 nM），对骨骼肌亚型 Na1.4（IC > 10 μM）和心肌亚型 Na1.5（IC > 10 μM）具有高选择性。Ca2a 并未显著改变 Na1.7 的电压依赖性激活或快速失活，但使其缓慢失活超极化。定点诱变分析表明，Ca2a 在结构域 II 的细胞外 S3-S4 连接区与 Na1.7 结合。同时，Ca2a 在福尔马林诱导的舔爪、热板试验和醋酸诱导的扭体等啮齿动物模型中剂量依赖性地减轻疼痛行为。本研究表明，Ca2a 是新型镇痛药药物开发的潜在先导分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2df/6198068/24a958b7cca6/fphar-09-01158-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2df/6198068/2e66982e8184/fphar-09-01158-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2df/6198068/dbc7ba733598/fphar-09-01158-g002.jpg
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