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Recent achievements in developing selective Gq inhibitors.
Medicinal Research Reviews ( IF 13.3 ) Pub Date : 2019-06-19 , DOI: 10.1002/med.21598
Hang Zhang 1 , Alexander L Nielsen 2 , Kristian Strømgaard 2
Affiliation  

G proteins are key mediators of G protein‐coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM‐254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q‐mediated signaling. Moreover, a peptide‐based G protein antagonist‐2A (GP‐2A), a 27‐residue peptide (27mer(I860A)) derived from phospholipase C‐β3 (PLC‐β3), and the small molecule BIM‐46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q‐selective inhibitors will expand our knowledge of the structure and function of G protein‐mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.

中文翻译:

在开发选择性Gq抑制剂方面的最新成就。

G蛋白是G蛋白偶联受体(GPCR)信号传导的关键介质,可促进大量重要的生理过程。与GPCR功能的其他方面相比,人们对G蛋白的作用了解得少得多,这在很大程度上是由于缺乏有效的和选择性的G蛋白抑制剂。天然环状二肽肽YM-254890和FR900359是Gq亚家族中极少数已知的选择性抑制剂中的两种,在Gq介导的信号传导研究中被用作独特的药理学工具 。此外,基于肽的G蛋白拮抗剂2A(GP-2A),衍生自磷脂酶C-β3(PLC-β3)的27残基肽(27mer(I860A))和小分子BIM-46187也已被分离出来。表征为选择性G q过去5年内的抑制剂。在这篇综述中,我们重点介绍了这些选择性Gq抑制剂在化学合成,表征和作用机理方面的最新进展 。G q选择性抑制剂的开发和应用 将扩展我们对G蛋白介导的信号传导的结构和功能的了解,阐明其他G蛋白类别抑制剂的开发,并为G蛋白疾病的药物研发提供帮助牵连其中,包括各种形式的癌症。
更新日期:2019-06-19
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