Drug discovery targeting Nav1.8: Structural insights and therapeutic potential

IF 6.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Current Opinion in Chemical Biology Pub Date : 2024-10-17 DOI:10.1016/j.cbpa.2024.102538
Huan Wang , Jian Huang , Jie Zang , Xueqin Jin , Nieng Yan
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Abstract

Voltage-gated sodium (Nav) channels are crucial in transmitting action potentials in neurons. The tetrodotoxin-resistant subtype Nav1.8 is predominantly expressed in the peripheral nervous system, offering a unique opportunity to design selective inhibitors for pain relief. A number of compounds have been reported to specifically block Nav1.8. Among these, VX-548 is already in regulatory review for the treatment of moderate-to-severe acute pain and holds the promise to be the first non-opioid pain killer over the past twenty years. Recent structural studies using cryogenic electron microscopy (cryo-EM) and structure-based predictive modeling have provided unprecedented insights into the structural pharmacology of Nav1.8. In this review, we summarize the latest developments in Nav1.8-selective inhibitors, focusing on the druggable sites and mechanisms that confer subtype specificity. These structural insights highlight the potential for Nav1.8 inhibitors to deliver non-addictive pain management, thus illuminating the avenue to next-generation analgesic development.
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以 Nav1.8 为靶点的药物发现:结构见解和治疗潜力
电压门控钠(Nav)通道是神经元传递动作电位的关键。耐河豚毒素亚型 Nav1.8 主要在外周神经系统中表达,这为设计用于缓解疼痛的选择性抑制剂提供了独特的机会。据报道,许多化合物都能特异性阻断 Nav1.8。其中,VX-548 已进入监管审查阶段,用于治疗中度至重度急性疼痛,有望成为过去二十年来首个非阿片类止痛药。最近利用低温电子显微镜(cryo-EM)和基于结构的预测模型进行的结构研究为 Nav1.8 的结构药理学提供了前所未有的见解。在这篇综述中,我们总结了 Nav1.8 选择性抑制剂的最新进展,重点介绍了赋予亚型特异性的可药用位点和机制。这些结构性见解凸显了 Nav1.8 抑制剂提供非成瘾性疼痛治疗的潜力,从而为下一代镇痛药的开发指明了道路。
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来源期刊
Current Opinion in Chemical Biology
Current Opinion in Chemical Biology 生物-生化与分子生物学
CiteScore
13.30
自引率
1.30%
发文量
113
审稿时长
74 days
期刊介绍: COCHBI (Current Opinion in Chemical Biology) is a systematic review journal designed to offer specialists a unique and educational platform. Its goal is to help professionals stay informed about the growing volume of information in the field of Chemical Biology through systematic reviews.
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