特异阻断乙酰胆碱受体的海南产α*-芋螺毒素的研究

Hainan α*-conotoxins target nicotinic acetylcholine receptors

国际上被誉为"海洋药物宝库"的芋螺毒素(CTx),具有特异结合动物体内各种离子通道和受体的特殊功能。其中的α*-芋螺毒素(α*-CTxs)能特异性地作用于乙酰胆碱受体(n ACh Rs),对其亚型具有极高的选择性阻断活性。不同的亚基组合形成的各种乙酰胆碱受体亚型,在正常健康状态下和多种疾病状态下起着很重要的生理和病理学功能,这些功能至今尚不很清楚,因而发现和开发各种亚型的选择性分子探针,如α*-CTxs将有助于阐释各个亚型的精细结构和功能。深入研究特异阻断乙酰胆碱受体不同亚型的α*-CTxs的结构与功能,及其与受体相互作用的机理具有很重要的科学意义,将有助于研发出与n ACh Rs相关的多种疑难杂症的治疗药物,包括神经痛、癌症化疗、成瘾、痴呆、重症肌无力、精神分裂症、癫痫、乳腺癌、肺癌、脑脊髓炎,以及其他神经疾病等。近年来,我们实验室经过大量筛选研究,鉴定出5个海南产新颖α*-芋螺毒素,对它们的人工合成、三维结构、作用靶点、与受体相互作用机制、药理药效等进行了深入的研究。现对上述特异阻断乙酰胆碱受体不同亚型的5个海南产α*-芋螺毒素的研究进展和应用前景进行综述。

Conotoxins（conopeptides, CTxs） are praised as ＂Marine drug mine＂, which target various ion channels and receptors of animal kingdom. Among them, α＊-conotoxins（α＊-CTxs） are effective antagonists of subtypes of nicotinic acetylcholine receptors（n ACh Rs） with high selectivity. Different combinations of n ACh R subunits form subtypes of n ACh Rs that are important in normal physiology, and in a wide range of disease states. Understanding of these functions may be greatly facilitated by discovery and characterization of selective α＊-CTxs probes. Mechanistic insight into the structure, function and receptor interaction of α＊-CTxs may serve as a platform for the development of selective medications for many n ACh Rs-related diseases, including neuralgia, chemotherapeutics, addiction, Alzheimer＇s disease（AD）, myasthenia gravis, schizophrenia, epilepsy, breast and lung carcinoma, experimental autoimmune encephalomyelitis（EAE） etc. Previously, we have identified five novel α＊-conotoxins from Hainan cone snails targeting different n ACh R subtypes, of which synthesis, 3-dimensional structure, target and interaction with receptors were investigated systematically. This review will focus on their characteristics and application prospects.