Li Xiao, Tae Han-Shen, Chu Yanyan, Jiang Tao, Adams David J, Yu Rilei
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia.
Pharmacol Ther. 2021 Jun;222:107792. doi: 10.1016/j.pharmthera.2020.107792. Epub 2020 Dec 10.
α-Conotoxins are disulfide-rich and well-structured peptides, most of which can block nicotinic acetylcholine receptors (nAChRs) with exquisite selectivity and potency. There are various nAChR subtypes, of which the α9α10 nAChR functions as a heteromeric ionotropic receptor in the mammalian cochlea and mediates postsynaptic transmission from the medial olivocochlear. The α9α10 nAChR subtype has also been proposed as a target for the treatment of neuropathic pain and the suppression of breast cancer cell proliferation. Therefore, α-conotoxins targeting the α9α10 nAChR are potentially useful in the development of specific therapeutic drugs and pharmacological tools. Despite dissimilarities in their amino acid sequence and structures, these conopeptides are potent antagonists of the α9α10 nAChR subtype. Consequently, the activity and stability of these peptides have been subjected to chemical modifications. The resulting synthetic analogues have not only functioned as molecular probes to explore ligand binding sites of the α9α10 nAChR, but also have the potential to become candidates for drug development. From the perspectives of medicinal chemistry and pharmacology, we highlight the structure and function of the α9α10 nAChR and review studies of α-conotoxins targeting it, including their three-dimensional structures, structure optimization strategies, and binding modes at the α9α10 nAChR, as well as their therapeutic potential.
α-芋螺毒素是富含二硫键且结构良好的肽，其中大多数能够以极高的选择性和效力阻断烟碱型乙酰胆碱受体（nAChRs）。存在多种nAChR亚型，其中α9α10 nAChR在哺乳动物耳蜗中作为异聚离子型受体发挥作用，并介导来自内侧橄榄耳蜗束的突触后传递。α9α10 nAChR亚型也被提议作为治疗神经性疼痛和抑制乳腺癌细胞增殖的靶点。因此，靶向α9α10 nAChR的α-芋螺毒素在开发特定治疗药物和药理学工具方面具有潜在用途。尽管这些芋螺肽在氨基酸序列和结构上存在差异，但它们都是α9α10 nAChR亚型的强效拮抗剂。因此，这些肽的活性和稳定性已接受化学修饰。所得的合成类似物不仅可作为分子探针来探索α9α10 nAChR的配体结合位点，还具有成为药物开发候选物的潜力。从药物化学和药理学的角度出发，我们重点介绍α9α10 nAChR的结构和功能，并综述针对它的α-芋螺毒素的研究，包括它们的三维结构、结构优化策略、在α9α10 nAChR上的结合模式以及它们的治疗潜力。
