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一种对TDRD3的双价抑制剂,可以抑制甲基化G3BP1的相分离

Wei-Wei Fan¹, Tian Xu¹, Jia Gao¹

¹The First Affiliated Hospital & School of Life Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. kruan@ustc.edu.cn.

Chemical communications (Cambridge, England)

|December 21, 2023

概括

研究人员开发了一种双价抑制剂,以阻止驱动压力颗粒形成的蛋白相互作用. 这种抑制剂增强了结合亲和力,抑制了压力颗粒的生长,为涉及这些细胞结构的疾病提供了新的治疗策略.

科学领域:

生物化学生化学
细胞生物学细胞生物学
分子医学是分子医学.

背景情况:

没有膜的器官通过多价值体弱相互作用形成.
控制这些与小分子的相互作用是具有挑战性的.
压力颗粒 (SG) 是关键的无膜有机体,与各种疾病有关.

研究的目的:

研究一种双价抑制剂在SG组合中调节多价相互作用的潜力.
阻止G3BP1 (G3BP应力颗粒组装因子1) 通过TDRD3 (Tudor域含蛋白3) 的招募.
评估抑制剂在抑制SG形成和生长方面的有效性.

主要方法:

一种双价小分子抑制剂的设计和合成.
生物化学试验以测量与TDRD3的结合亲和力.
在实验室中使用G3BP1,TDRD3和RNA进行相位分离试验.
基于细胞的测试观察压力颗粒形成和生长抑制.

主要成果:

双价抑制剂有效地阻止了G3BP1.1上甲基化氨酸的TDRD3招募.
与单价抑制剂相比,双价抑制剂对TDRD3.3具有显著增强的结合亲和力.
该抑制剂抑制了G3BP1,TDRD3和RNA的相分离,导致细胞中受阻的压力颗粒生长.

结论:

双价抑制剂代表了在SG组装中调解多价相互作用的有希望的策略.
这种方法为与异常SG形成相关的疾病提供了一种新的治疗途径.
潜在的应用包括针对应力颗粒的组合化疗策略.

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