Data from: Dicarba a-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors

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Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, alpha-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat alpha9alpha10 and alpha3beta4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide's innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at gamma-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the alpha9alpha10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide's potent analgesic activity.

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芋螺毒素（Conotoxins）已成为新型治疗性镇痛药开发的极具价值的先导化合物。这类肽类物质从芋螺属（Conus）海洋软体动物中分离得到，对可兴奋组织的受体与离子通道具有极为精准的选择性。其中一种肽类——α-芋螺毒素Vc1.1，是一种带有锁合二硫键骨架的16肽。尽管Vc1.1已作为强效镇痛先导化合物被发现，但其分子靶点与作用机制至今仍未阐明。本研究阐述了利用烯烃复分解反应区域选择性合成Vc1.1二碳桥类似物的方法。本研究评估了这些肽类对爪蟾卵母细胞（Xenopus oocytes）中表达的大鼠α9α10与α3β4烟碱型乙酰胆碱受体（nAChR）的乙酰胆碱诱发电流的抑制能力，同时检测了它们对分离的大鼠背根神经节（Dorsal Root Ganglion, DRG）神经元中高电压激活（HVA）钙通道电流的抑制作用。本研究通过核磁共振（NMR）波谱学测定了这些肽类的溶液结构。值得注意的是，本研究发现，用二碳桥区域选择性取代天然的胱氨酸骨架，可对环肽针对不同受体的固有生物活性进行精准调控。2,8-二碳桥Vc1.1异构体对γ-氨基丁酸（GABAB）G蛋白偶联受体仍保留活性，而异构体3,16-二碳桥Vc1.1肽则对α9α10 nAChR亚型保留活性。这些具有单一靶向活性的类似物，将有助于阐明该肽类强效镇痛活性背后的生物学靶点。