CRIOBE, UAR CNRS-EPHE-UPVD 3278, Université de Perpignan Via Domitia, 58 Avenue Paul Alduy, 66860 Perpignan, France.
Faculty of Medicine, Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Nußbaumstraße 26, 80336 Munich, Germany.
Mar Drugs. 2023 Jun 9;21(6):356. doi: 10.3390/md21060356.
α-Conotoxins are well-known probes for the characterization of the various subtypes of nicotinic acetylcholine receptors (nAChRs). Identifying new α-conotoxins with different pharmacological profiles can provide further insights into the physiological or pathological roles of the numerous nAChR isoforms found at the neuromuscular junction, the central and peripheral nervous systems, and other cells such as immune cells. This study focuses on the synthesis and characterization of two novel α-conotoxins obtained from two species endemic to the Marquesas Islands, namely and . Both species prey on fish, and their venom is considered a rich source of bioactive peptides that can target a wide range of pharmacological receptors in vertebrates. Here, we demonstrate the versatile use of a one-pot disulfide bond synthesis to achieve the α-conotoxin fold [Cys 1-3; 2-4] for GaIA and AdIA, using the 2-nitrobenzyl (NBzl) protecting group of cysteines for effective regioselective oxidation. The potency and selectivity of GaIA and AdIA against rat nicotinic acetylcholine receptors were investigated electrophysiologically and revealed potent inhibitory activities. GaIA was most active at the muscle nAChR (IC = 38 nM), whereas AdIA was most potent at the neuronal α6/3 β2β3 subtype (IC = 177 nM). Overall, this study contributes to a better understanding of the structure-activity relationships of α-conotoxins, which may help in the design of more selective tools.
α- 神经毒素是鉴定各种烟碱型乙酰胆碱受体 (nAChR) 亚型的重要探针。鉴定具有不同药理学特征的新型 α- 神经毒素可以进一步深入了解在神经肌肉接头、中枢和外周神经系统以及其他细胞（如免疫细胞）中发现的众多 nAChR 同工型的生理或病理作用。本研究关注的是从马克萨斯群岛特有的两种物种中获得的两种新型 α- 神经毒素的合成和表征，即 和 。这两个物种都以鱼类为食，其毒液被认为是生物活性肽的丰富来源，这些肽可以靶向脊椎动物中广泛的药理学受体。在这里，我们展示了一种一锅法二硫键合成方法的多功能性，该方法用于实现 GaIA 和 AdIA 的 α- 神经毒素折叠 [Cys1-3;2-4]，使用半胱氨酸的 2- 硝基苄基 (NBzl) 保护基实现有效的区域选择性氧化。我们用电生理学方法研究了 GaIA 和 AdIA 对大鼠烟碱型乙酰胆碱受体的效力和选择性，并揭示了它们具有很强的抑制活性。GaIA 在肌肉 nAChR 上最活跃（IC = 38 nM），而 AdIA 在神经元 α6/3β2β3 亚型上最有效（IC = 177 nM）。总的来说，这项研究有助于更好地了解 α- 神经毒素的结构-活性关系，这可能有助于设计更具选择性的工具。
