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

doi:10.6023/A25040105

Acta Chimica Sinica ›› 2025, Vol. 83 ›› Issue (7): 755-772.DOI: 10.6023/A25040105 Previous Articles Next Articles

Review

靶向酸敏感离子通道的毒素肽: 镇痛机制与生物合成开发

李海婷^a^,^b, 吴小余^a^,^*(), 曹春阳^b^,^*()

^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

投稿日期:2025-04-03 发布日期:2025-07-28

作者简介:

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, 2000~2005年于中科院上海有机化学研究所攻读博士, 2006~2008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, 1998~2001年于中科院上海有机化学研究所攻读博士, 2001~2005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, 2005~2006年转至美国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.

基金资助:
中国科学院战略性先导科技专项(XDB1060000)

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

Haiting Li^a^,^b, Xiaoyu Wu^a^,^*(), Chunyang Cao^b^,^*()

^a Department of Chemistry, College of Science, Shanghai University, Shanghai 200444, China
^b State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

Received:2025-04-03 Published:2025-07-28
Contact: *E-mail: wuxy@shu.edu.cn; ccao@mail.sioc.ac.cn;E-mail: ccao@mail.sioc.ac.cn
Supported by:
Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1060000)

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 anti-inflammatory 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 domains, 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., the DisCoTune system). Pichia pastoris enables secretory expression with low immunogenicity by post-translational modification systems and α-mating factor signal peptides. 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 modifications like PEGylation to improve the 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

Cite this article

Haiting Li, Xiaoyu Wu, Chunyang Cao. Targeting Acid-Sensing Ion Channels with Toxin Peptides: Analgesic Mechanisms and Biosynthesis Development[J]. Acta Chimica Sinica, 2025, 83(7): 755-772.

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名称	来源	用药方式	作用靶点/机制	主要适应症	临床状态	备注
Cobratide (克痛宁)	中华眼镜蛇 (Naja atra)	静脉注射/口服	烟碱型乙酰胆碱受体阻断剂	慢性关节痛、坐骨神经痛、神经性头痛	已上市	国药准字H53022101^[27]
Ziconotide (Prialt®)	Conus magus	鞘内注射	Cav2.2通道阻断剂	严重慢性疼痛	已上市	New Drug Application (NDA): 021060^[28]
μ-TRTX-Hhn1b (Halneuron)	Ornithoctonus hainana	皮下注射	电压门控钠通道 Nav1.7抑制剂	化疗性神经性疼痛	II期临床	ClinicalTrials.gov ID: NCT06848348^[29]
Tetrodotoxin	pufferfish	肌内注射/皮下注射	电压门控钠通道 Nav阻断剂	中度或重度癌症疼痛、化疗性神经性疼痛	Ⅱ/Ⅲ期临床	ClinicalTrials.gov ID: NCT00726011/NCT00725114/NCT01655823^[29]
ACV-1 (a-Vc1.1)	Conus victoriae	皮下注射	GABA_B受体激活剂	糖尿病性神经病变疼痛	II期临床	因缺乏疗效而停止^[30]
Contulakin-G (CGX-1160)	Conus geographus	鞘内注射	神经降压素受体激活剂	神经病理性疼痛	II期临床	因开发商公司破产而停止^[30]
Leconotide (ω-conotoxin CVID)	Conus catus	鞘内注射	Cav2.2通道阻断剂	神经病理性疼痛	Ⅰ/II期临床	因开发商公司破产而停止^[30]
Xen 2174 (c-CTX MrIA)	Conus marmoreus	鞘内注射	作用于去甲肾上腺素转运体	术后疼痛	II b期临床	已停止^[30]

名称	来源	用药方式	作用靶点/机制	主要适应症	临床状态	备注
Cobratide (克痛宁)	中华眼镜蛇 (Naja atra)	静脉注射/口服	烟碱型乙酰胆碱受体阻断剂	慢性关节痛、坐骨神经痛、神经性头痛	已上市	国药准字H53022101^[27]
Ziconotide (Prialt®)	Conus magus	鞘内注射	Cav2.2通道阻断剂	严重慢性疼痛	已上市	New Drug Application (NDA): 021060^[28]
μ-TRTX-Hhn1b (Halneuron)	Ornithoctonus hainana	皮下注射	电压门控钠通道 Nav1.7抑制剂	化疗性神经性疼痛	II期临床	ClinicalTrials.gov ID: NCT06848348^[29]
Tetrodotoxin	pufferfish	肌内注射/皮下注射	电压门控钠通道 Nav阻断剂	中度或重度癌症疼痛、化疗性神经性疼痛	Ⅱ/Ⅲ期临床	ClinicalTrials.gov ID: NCT00726011/NCT00725114/NCT01655823^[29]
ACV-1 (a-Vc1.1)	Conus victoriae	皮下注射	GABA_B受体激活剂	糖尿病性神经病变疼痛	II期临床	因缺乏疗效而停止^[30]
Contulakin-G (CGX-1160)	Conus geographus	鞘内注射	神经降压素受体激活剂	神经病理性疼痛	II期临床	因开发商公司破产而停止^[30]
Leconotide (ω-conotoxin CVID)	Conus catus	鞘内注射	Cav2.2通道阻断剂	神经病理性疼痛	Ⅰ/II期临床	因开发商公司破产而停止^[30]
Xen 2174 (c-CTX MrIA)	Conus marmoreus	鞘内注射	作用于去甲肾上腺素转运体	术后疼痛	II b期临床	已停止^[30]

毒素名称	来源生物	靶向ASIC亚型	调节方式	作用特点
APETx2	海葵	ASIC3	抑制	可能与孔阻塞相关, 非pH依赖
Hi1a	蜘蛛	ASIC1a	抑制	PcTx1的串联体, 更强效长效
Mambalgin	曼巴蛇	ASIC1a、1b	抑制	干扰亚基构象转变, pH依赖
MitTx	珊瑚蛇	ASIC1a	激活	稳定通道开放构象, 组成型激活
PcTx1	蜘蛛	ASIC1a	抑制	稳定通道脱敏构象, pH依赖

毒素名称	来源生物	靶向ASIC亚型	调节方式	作用特点
APETx2	海葵	ASIC3	抑制	可能与孔阻塞相关, 非pH依赖
Hi1a	蜘蛛	ASIC1a	抑制	PcTx1的串联体, 更强效长效
Mambalgin	曼巴蛇	ASIC1a、1b	抑制	干扰亚基构象转变, pH依赖
MitTx	珊瑚蛇	ASIC1a	激活	稳定通道开放构象, 组成型激活
PcTx1	蜘蛛	ASIC1a	抑制	稳定通道脱敏构象, pH依赖

靶向酸敏感离子通道的毒素肽: 镇痛机制与生物合成开发

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

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