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通过计算模拟探索蝎毒镇痛-抗肿瘤肽对人电压门控钠离子通道 1.4 和 1.5 诱导的副作用的关键影响因素。

Exploring the Pivotal Components Influencing the Side Effects Induced by an Analgesic-Antitumor Peptide from Scorpion Venom on Human Voltage-Gated Sodium Channels 1.4 and 1.5 through Computational Simulation.

机构信息

School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.

Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.

出版信息

Toxins (Basel). 2022 Dec 31;15(1):33. doi: 10.3390/toxins15010033.

Abstract

Voltage-gated sodium channels (VGSCs, or Na) are important determinants of action potential generation and propagation. Efforts are underway to develop medicines targeting different channel subtypes for the treatment of related channelopathies. However, a high degree of conservation across its nine subtypes could lead to the off-target adverse effects on skeletal and cardiac muscles due to acting on primary skeletal muscle sodium channel Na1.4 and cardiac muscle sodium channel Na1.5, respectively. For a long evolutionary process, some peptide toxins from venoms have been found to be highly potent yet selective on ion channel subtypes and, therefore, hold the promising potential to be developed into therapeutic agents. In this research, all-atom molecular dynamic methods were used to elucidate the selective mechanisms of an analgesic-antitumor β-scorpion toxin (AGAP) with human Na1.4 and Na1.5 in order to unravel the primary reason for the production of its adverse reactions on the skeletal and cardiac muscles. Our results suggest that the rational distribution of residues with ring structures near position 38 and positive residues in the C-terminal on AGAP are critical factors to ensure its analgesic efficacy. Moreover, the substitution for residues with benzene is beneficial to reduce its side effects.

摘要

电压门控钠离子通道(VGSCs,或 Na)是动作电位产生和传播的重要决定因素。目前正在努力开发针对不同通道亚型的药物,以治疗相关的通道病。然而,由于其九个亚型之间存在高度的保守性,因此可能会对骨骼和心肌产生脱靶的不良反应,分别作用于主要的骨骼肌钠离子通道 Na1.4 和心肌钠离子通道 Na1.5。在漫长的进化过程中,从毒液中发现了一些肽毒素,对离子通道亚型具有高度的效力和选择性,因此具有开发成治疗剂的巨大潜力。在这项研究中,使用全原子分子动力学方法阐明了一种具有镇痛抗肿瘤作用的β-蝎毒素(AGAP)与人类 Na1.4 和 Na1.5 的选择性机制,以揭示其对骨骼和心肌产生不良反应的主要原因。我们的研究结果表明,在位置 38 附近具有环状结构的残基和 C 末端的正残基的合理分布是确保其镇痛效果的关键因素。此外,苯取代残基有利于降低其副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0612/9864070/d44752461ad2/toxins-15-00033-g011.jpg

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