在人类基因组中对催化氨酸的全球反应性概述,用于共价抑制剂的发展
Guanghui Tang1, Wei Wang2, Chengjun Zhu3
1Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore.
Angewandte Chemie (International ed. in English)
|January 22, 2024
概括
研究人员开发了使用基硫酸用于广泛基因组分析的新型氨酸反应探针. 这些探针可以创建有针对性的共价抑制剂,以提高功效和细胞活性.
科学领域:
- 化学生物学 化学生物学
- 药用化学 医学化学
- 蛋白质组学是指蛋白质组学.
背景情况:
- 有针对性的共价抑制剂 (TCI) 正在发展,但有限的素反应性氨基阻碍了细胞活性 TCI 的发展.
- 催化溶是关键的目标,但全球分析方法很少.
研究的目的:
- 开发基于素反应活性的新型探针 (ABP) 用于全球基因组反应性概况.
- 创建可调节的共价探头和具有增强性能的新型TCI.
主要方法:
- 合成氨酸反应性烯硫酸盐 (ArOSO2F) 和可逆共价探针.
- 利用X射线晶体学和质谱学来验证共价接触.
- 进行了全球基因组概况 (>300个基因酶) 的化学蛋白质学研究.
主要成果:
- 通过ArOSO2F探针证明了SRC激酶催化的成功共价修饰.
- 实现了300多种内源性激酶的广泛反应性概况.
- 通过将探针集成到VX-680中,生成了新的TCI,显示出强大的体外和细胞活性.
结论:
- 烯硫酸盐为开发氨酸反应型ABP和TCI提供了一个多功能平台.
- 开发的探测器提供了一种通用策略,用于在基因组中准催化溶酶.
- 这项工作促进了TCI开发和化学蛋白质组分析能力的发展.
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