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使用基于细胞的NanoBit试验发现RGS2-FBXO44相互作用抑制剂

Sadikshya Aryal¹, Cindy Shi Yee Wong², Harrison J McNabb¹

¹Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.

Molecular pharmacology

|April 8, 2025

概括

研究人员发现了一种新型化合物,可以抑制RGS2和FBXO44之间的相互作用,从而增加RGS2蛋白水平. 这一发现为与低RGS2相关的疾病提供了新的治疗策略,例如高血压.

科学领域:

生物化学生物化学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

调节G蛋白信号传递 (RGS) 蛋白在细胞信号传递中至关重要,它们的功能障碍与各种疾病有关.
由于缺乏可用药物的口袋和酶活性,对RGS蛋白的治疗向是困难的.
稳定RGS2蛋白水平为高血压,心力衰竭和喘等疾病提供了有希望的治疗途径.

研究的目的:

开发一种用于识别抑制RGS2蛋白降解的小分子的策略.
发现RGS2-FBXO44相互作用的抑制剂,这是一种关键的E3结合酶复合物,参与RGS2降解.
验证一种新型化合物作为提高RGS2蛋白水平的工具.

主要方法:

开发一个NanoLuc二进制技术 (NanoBiT) 试验来检测RGS2-FBXO44相互作用.
从蛋白质与蛋白质相互作用碎片库中选1600种化合物.
使用siRNA介导的淘汰来确认作用机制.

主要成果:

确定了一种新型化合物,被指定为化合物10,该化合物抑制RGS2-FBXO44相互作用,功效为19.6微米.
化合物10直接与RGS2结合,使其稳定并增加其蛋白质水平.
观察到的RGS2水平的增加取决于FBXO44,因为其敲击减弱了该化合物的作用.

结论:

化合物10是第一个被确定用于RGS2-FBXO44相互作用的小分子抑制剂.
这项研究证明了使用RGS2-FBXO44相互作用抑制剂来增加RGS2蛋白水平的概念证明.
开发具有这种机制的化合物有可能治疗RGS2相关的疾病,如高血压,心力衰竭和喘.

关键词:

高通量选的高通量选蛋白质体中的降解.在RGS蛋白质中.

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