Shengrong Pei, Nan Wang, Zaoli Mei, Dongting Zhangsun, David J Craik, J Michael McIntosh, Xiaopeng Zhu, Sulan Luo
{"title":"Conotoxins Targeting Voltage-Gated Sodium Ion Channels.","authors":"Shengrong Pei, Nan Wang, Zaoli Mei, Dongting Zhangsun, David J Craik, J Michael McIntosh, Xiaopeng Zhu, Sulan Luo","doi":"10.1124/pharmrev.123.000923","DOIUrl":null,"url":null,"abstract":"<p><p>Voltage-gated sodium (Na<sub>V</sub>) 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 Na<sub>V</sub> 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 Na<sub>V</sub> 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 Na<sub>V</sub> channels or as drug leads for neurologic diseases related to Na<sub>V</sub> channels. Accordingly, discovering or designing conotoxins targeting Na<sub>V</sub> 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 Na<sub>V</sub> channel-targeted conotoxins, focusing on their structures, activities, and designed modifications, with a view toward expanding their applications. SIGNIFICANCE STATEMENT: Na<sub>V</sub> channels are crucial in various neurologic diseases. Some conotoxins selectively target Na<sub>V</sub> 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 Na<sub>V</sub> channels have both immediate research value and promising future application prospects.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331937/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacological Reviews","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/pharmrev.123.000923","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
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.
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。许多毒液肽会选择性地作用于 NaV 通道。其中包括芋螺毒素,芋螺毒素是锥螺为捕捉猎物或自卫而分泌的神经毒素,同时也是识别和/或治疗人类疾病的重要药理学工具。芋螺毒素通常含有两个或三个二硫键,这些内部交叉架使芋螺毒素具有紧凑、明确的结构和高稳定性。在含有三个二硫键的芋螺毒素中,有些可选择性地靶向哺乳动物的 NaV 通道,并能阻断、刺激或调节这些通道。这类芋螺毒素具有巨大的潜力,可作为研究 NaV 通道功能和特性的药理学工具,或作为治疗与 NaV 通道有关的神经系统疾病的药物线索。因此,发现或设计具有高效力和高选择性的针对 NaV 通道的芋螺毒素非常重要。氨基酸序列、二硫键连接和三维结构是影响芋螺毒素生物活性的关键因素,对芋螺毒素进行有针对性的合成修饰可大大提高其活性和选择性。本综述探讨了以 NaV 通道为靶标的芋螺毒素,重点关注其结构、活性和设计修饰,以期扩大其应用范围。意义声明 NaV 通道在各种神经系统疾病中至关重要。一些芋螺毒素可选择性地靶向 NaV 通道,导致阻断或激活,因此可用作研究通道特性和功能的药理学工具。芋螺毒素还具有开发药物先导的潜力。这些肽中的二硫键对稳定其结构非常重要,从而提高了特异性和药效。总之,靶向 NaV 通道的芋螺毒素既有直接的研究价值,又有广阔的应用前景。
期刊介绍:
Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.