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在人类细胞中绘制蛋白质相互作用景观,以实现完全功能化的小分子探针

Tohru Kambe¹, Bruno E Correia, Micah J Niphakis

¹The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

Journal of the American Chemical Society

|July 22, 2014

概括

这项研究引入了多样化的化学探针库,用于在人类细胞内识别药物点. 这些探测器有效地捕获和识别各种各样的蛋白质,推动了小分子药物发现.

科学领域:

化学生物学化学生物学
蛋白质组学是指蛋白质组学.
药物发现药物发现药物发现

背景情况:

现型查识别了影响细胞过程的分子,但在目标识别方面存在困难.
具有光反应组和亲和力手柄的功能齐全的探针为综合查和目标识别提供了解决方案.
细胞中这种探针的蛋白质相互作用的范围在很大程度上是未知的.

研究的目的:

综合和描述一个功能齐全的化学探针库.
探索这些探针在人体细胞中的蛋白质相互作用的范围.
评估这些探针对于目标识别和药理学研究的有用性.

主要方法:

使用Ugi-azide凝结反应合成一个大约60个成员的探针库.
加入迪亚齐林用于光反应交叉链接和基因用于亲和力丰富.
基于质谱的蛋白质组分析,以确定人体细胞中的探针结合蛋白质.
结构-活性关系研究和使用小分子配体的竞争分析.

主要成果:

一组多样化的细胞蛋白被确定为目标,包括酶,道,适配器/脚手架蛋白和功能不明的蛋白质.
许多已识别的蛋白质标缺乏之前描述的小分子联结体.
对于大多数相互作用,在探测器库中观察到明确的结构-活动关系.
试管蛋白相互作用被证实是特异性的,并且可以通过竞争的小分子来阻止.

结论:

完全功能化的小分子探测器可以有效地询问人类蛋白质组的不同部分.
这个探针库为目标识别和理解药物作用机制提供了有价值的工具.
这些发现支持了这种探针作为细胞生物学研究中的药理学工具的潜力.

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