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2025 25040105 - 25040105

DOI: https://doi.org/10.6023/A25040105

综述

靶向酸敏感离子通道的毒素肽：镇痛机制与生物合成开发

  • Li ,
  • Haiting ,
  • Xiaoyu ,
  • Chunyang
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  • a(上海大学 理学院化学系 上海 200444)
    b(中国科学院上海有机化学研究所 生命过程小分子调控全国重点实验室 上海 200032)
李海婷,女,上海大学和中科院上海有机化学研究所 2022 级联合培养有机化学专业硕士研究生, 主要研究方向为靶向离子通道的毒素多肽的生物合成和应用。吴小余,男,上海大学化学系教授,博士生导师,2000年-2005年于中科院上海有机化学研究所攻读博士,2006年-2008年于新加坡国立大学进行博士后研究,2008年进入上海大学工作至今,主要研究方向为不对称催化和医药中间体合成工艺开发。曹春阳, 男, 1998年-2001年于中科院上海有机化学研究所攻读博士,2001年-2005年在约翰霍普金斯大学医学院分子药理系从事博士后研究,2005年-2006转至美国 Salk 生物研究院结构生物学中心从事助理研究员,2006年至今为中国科学院上海有机化学研究所“百人计划”研究员, 上海市“浦江计划”获得者,主要研究方向为以NMR技术为主导,结合蛋白质晶体学,开展与肿瘤发生与发展、病毒感染相关的蛋白质与核酸结构与功能分子机制研究、天然产物活性分子筛选与药物分子设计。

收稿日期: 2025-04-03

  网络出版日期: 2025-06-04

基金资助

项目受中国科学院战略性先导科技专项 (XDB1060000)资助

收起

Targeting Acid-Sensing Ion Channels with Toxin Peptides: Analgesic Mechanisms and Biosynthesis Development

  • 李海婷 ,
  • 吴小余 ,
  • 曹春阳
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  • a(College of Science, Shanghai University, Shanghai 200444)
    b(State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032)

Received date: 2025-04-03

  Online published: 2025-06-04

Supported by

Strategic Priority Research Program of the Chinese Academy of sciences grant (XDB1060000)

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摘要

酸敏感离子通道（ASIC）在酸诱导的疼痛信号传导中发挥关键作用,其亚型特异性分布为开发精准镇痛药物提供了独特靶点,例如ASIC1a主要参与中枢敏化过程,ASIC3在外周炎性痛中起核心调控作用。传统镇痛药物因存在中枢副作用和靶点选择性不足等局限制约了临床应用,而天然毒素肽如PcTx1、Mambalgin和APETx2通过特异性结合ASIC胞外结构域并精确调控通道门控特性,可在纳摩尔级浓度水平实现高效镇痛且无成瘾性。本文系统阐述了ASIC的分子结构和门控机制,深入分析了代表性毒素肽的作用模式,继而梳理了毒素肽的生物合成及成药性优化策略,涵盖原核与真核表达系统的应用优化、化学修饰技术以及基因工程改造方法,最后探讨了毒素肽药物在临床转化过程中面临的挑战与可能的解决方案。随着多学科的发展和交叉应用,毒素肽药物有望突破传统镇痛治疗瓶颈。本文为基于离子通道靶点的创新镇痛剂研发提供了多维度的技术路线与理论支撑。

关键词： 酸敏感离子通道; ASIC; 毒素肽; 镇痛药物; 生物合成

本文引用格式

Li , Haiting , Xiaoyu , Chunyang . 靶向酸敏感离子通道的毒素肽：镇痛机制与生物合成开发[J]. 化学学报, 2025 : 25040105 -25040105 . DOI: 10.6023/A25040105

Abstract

Acid-sensing ion channels (ASICs), as proton-gated cation channels, play critical roles in acidosis-evoked pain signaling through their subtype-specific contributions to nociceptive pathways. ASIC1a predominantly drives central sensitization in neuropathic pain, while ASIC3 mediates peripheral inflammatory and musculoskeletal pain. While conventional analgesics, such as opioids and nonsteroidal antiinflammatory drugs, are limited by central side effects and poor selectivity, natural toxin peptides demonstrate remarkable therapeutic potential. PcTx1 (from tarantula venom), Mambalgin (snake-derived), and APETx2 (sea anemone toxin) exhibit nanomolar affinity for ASIC extracellular domains, effectively modulating channel gating to achieve potent analgesia without addiction risks. This review systematically elucidates the molecular architecture and gating mechanisms of ASICs, providing in-depth analysis of representative toxin peptides' mechanisms towards ASICs. PcTx1 stabilizes ASIC1a in a desensitized state through acidic pocket engagement, while Mambalgin-1 locks the thumb domain in resting state to inhibit activation. APETx2 is proposed to block ASIC3 via a basic amino acid cluster binding to the site between palm and wrist domain, as suggested by homology modeling. Biosynthetic strategies have advanced significantly, with Escherichia coli serving as a cost-effective platform for rapid production of disulfide-rich peptides through engineered oxidative folding pathways (e.g., DisCoTune system). Pichia pastoris enables secretory expression with low immunogenicity by post-translational modification systems and α-mating factor signals. For complex modifications, mammalian cells (e.g., chinese hamster ovary cells) provide precise folding and human-like post-translational processing. Key optimizations include solubility-enhancing tags (MBP, SUMO), affinity tags (poly-His), and chemical modification like PEGylation to improve pharmacokinetics of toxin peptides. Finally, the discussion extends to challenges in clinical translation of toxin peptide drugs, including incomplete ASIC subtype structural resolution and off-target effects. AI-driven design (AlphaFold2-predicted models) and stimuli-responsive nanocarriers (lipid-based systems) may address these limitations. With interdisciplinary advancements and cross-application of technologies, toxin peptides demonstrate promising potential to overcome limitations of conventional analgesic therapies.

Key words： Acid-sensing ion channel; ASIC; Toxin peptide; Analgesics; Biosynthesis

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