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ABPP-CoDEL:以活动为基础的蛋白质谱为指导,从DNA编码库中发现氨酸向共价抑制剂

Lulu Jiang¹, Sixiu Liu^2,3, Xinglong Jia¹

¹School of Pharmacy, Fudan University, Shanghai 201203, China.

Journal of the American Chemical Society

|October 19, 2023

概括

这项研究引入了针对氨酸的DNA编码化学库 (DEL),用于共价药物发现. 这种新的方法成功地确定了关键酶的选择性共价抑制剂,扩大了氨酸修饰的范围.

科学领域:

医学化学
化学生物学
药物发现

背景情况:

用DNA编码的化学库 (DEL) 是用于发现化合物的工具.
使用DEL的共价配体发现主要集中在囊残留物上.
非氨酸残留物是共价DEL应用的未经探索的领域.

研究的目的:

设计和评估氨酸向的共价DEL.
为了探索共价DEL的新修饰点.
确定针对蛋白质中的氨酸残留物的选择性共价抑制剂.

主要方法:

开发对氨酸反应的硫烯化物 (SF) 共价探针.
全蛋白质组反应性分析以确定可向的酶.
使用SF功能化的DEL来发现共价抑制剂.
基于活动的蛋白质组定型与共价DEL丰富 (ABPP-CoDEL) 结合.

主要成果:

已经成功设计并使用了6700万的氨酸向激光器.
确定了三种模型酶 (糖酸突变酶1,谷氨转移酶1,二基酶3) 是可以氨酸向的.
发现了具有独特作用模式的新型氨酸向性抑制剂.
在目标酶上发现反应性联体可访问的热点.

结论:

开发的ABPP-CoDEL策略可以发现针对各种蛋白质标的选择性共价结合剂.
协价DEL可以有效地准氨酸残留物,扩大药物发现的化学空间.
这种方法对推进共价药物发现工作具有重大潜力.

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