Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels
Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels
复制标题
通道病的药物开发：配体门控和电压门控离子通道的变构调节
DOI：
10.1021/acs.jmedchem.0c01304
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Yu Zhiyi
中科院分区：
文献类型：
--
作者：
Zhang Yanyun;Wang Ke;Yu Zhiyi
离子通道已被认为是治疗多种人类疾病的有希望的药物靶点。离子通道的功能可以通过变构调节剂进行微调，变构调节剂与通道相互作用并通过结合到与正构配体空间离散的位点来调节其活性。在选择性和安全性方面，正向和负向变构调节剂比传统的正向激动剂和拮抗剂具有许多潜在的治疗优势。本专题综述重点介绍了配体门控和电压门控离子通道的代表性变构调节剂的发现，特别讨论了它们的识别、位置和在治疗一系列通道病中的治疗用途。此外，还简要描述了所选离子通道的结构和功能，以帮助通道调制器的合理设计。总体而言，变构调节代表了一种创新的靶向方法，相应的调节剂为靶向配体门控和电压门控离子通道的新型疗法提供了丰富但具有挑战性的前景。
Ion channels have been characterized as promising drug targets for treatment of numerous human diseases. Functions of ion channels can be fine-tuned by allosteric modulators, which interact with channels and modulate their activities by binding to sites spatially discrete from those of orthosteric ligands. Positive and negative allosteric modulators have presented a plethora of potential therapeutic advantages over traditionally orthosteric agonists and antagonists in terms of selectivity and safety. This thematic review highlights the discovery of representative allosteric modulators for ligand-gated and voltage-gated ion channels, discussing in particular their identifications, locations, and therapeutic uses in the treatment of a range of channelopathies. Additionally, structures and functions of selected ion channels are briefly described to aid in the rational design of channel modulators. Overall, allosteric modulation represents an innovative targeting approach, and the corresponding modulators provide an abundant but challenging landscape for novel therapeutics targeting ligand-gated and voltage-gated ion channels.