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Abstract：
Voltage-gated sodium (NaV) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases, such as epilepsy, neuropathic pain, psychosis, autism, and cardiac arrhythmia. Many venom peptides selectively act on NaV channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense but which are also valuable pharmacological tools for the identification and/or treatment of human diseases. Typically, conotoxins contain two or three disulfide bonds, and these internal crossbraces contribute to conotoxins having compact, well defined structures and high stability. Of the conotoxins containing three disulfide bonds, some selectively target mammalian NaV channels and can block, stimulate, or modulate these channels. Such conotoxins have great potential to serve as pharmacological tools for studying the functions and characteristics of NaV channels or as drug leads for neurologic diseases related to NaV channels. Accordingly, discovering or designing conotoxins targeting NaV channels with high potency and selectivity is important. The amino acid sequences, disulfide bond connectivity, and three-dimensional structures are key factors that affect the biological activity of conotoxins, and targeted synthetic modifications of conotoxins can greatly improve their activity and selectivity. This review examines NaV channel-targeted conotoxins, focusing on their structures, activities, and designed modifications, with a view toward expanding their applications. SIGNIFICANCE STATEMENT: NaV channels are crucial in various neurologic diseases. Some conotoxins selectively target NaV channels, causing either blockade or activation, thus enabling their use as pharmacological tools for studying the channels\' characteristics and functions. Conotoxins also have promising potential to be developed as drug leads. The disulfide bonds in these peptides are important for stabilizing their structures, thus leading to enhanced specificity and potency. Together, conotoxins targeting NaV channels have both immediate research value and promising future application prospects.
摘要：
电压门控钠（NaV）通道与动作电位的产生和传递密切相关，这些通道的功能障碍可能会导致神经系统疾病，如癫痫，神经性疼痛,精神病,自闭症和心律失常.许多毒液肽选择性地作用于NaV通道。这些包括香菇毒素,它们是由蜗牛分泌的神经毒素，用于捕获猎物或自卫，但是它们也是用于识别和/或治疗人类疾病的有价值的药理学工具。通常,conotoxins含有两个或三个二硫键，这些内部交叉括号有助于conotoxins具有紧密的，明确的结构和高稳定性。在含有三个二硫键的芋螺毒素中，一些选择性靶向哺乳动物NaV通道，刺激,或调节这些频道。这样的芋螺毒素具有作为用于研究NaV通道的功能和特征的药理学工具或作为与NaV通道相关的神经疾病的药物线索的巨大潜力。因此，发现或设计具有高效力和选择性的靶向NaV通道的螺毒素是重要的。氨基酸序列,二硫键连接，三维结构是影响芋螺毒素生物活性的关键因素，和有针对性的合成改性的芋螺毒素可以大大提高其活性和选择性。这篇综述研究了NaV通道靶向的螺毒素，专注于它们的结构，活动和设计的修改，以扩大其应用范围。意义声明NaV通道在各种神经系统疾病中至关重要。一些芋螺毒素选择性地靶向NaV通道，导致封锁或激活，从而使它们能够用作药理学工具来研究通道的特性和功能。二恶英毒素也具有被开发为药物先导物的有希望的潜力。这些肽中的二硫键对于稳定它们的结构很重要，从而导致增强的特异性和效力。一起,以NaV通道为靶点的芋螺毒素既有研究价值,也有很好的应用前景。
