在活细胞中无缩,有针对性的共价药物发现
Kevin D Dong1, Qing Yu1, Ka Yang1
1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
ACS chemical biology
|November 18, 2025
概括
我们开发了CysDig,这是一个用于活细胞药物发现的新型化学蛋白质组学平台. 这种方法有效地识别了共价结合剂和化合物诱导的蛋白质降解,推动了向的共价药物开发.
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:
- 使用质谱学的基于活细胞活动的蛋白质概况 (ABPP) 量化了化合物反应性,但对于关键目标通常没有完整的数据.
- 现有的方法不允许在同一试验中同时测量化合物诱导的蛋白质变化.
研究的目的:
- 开发一种无缩化学蛋白质组学平台,用于在活细胞中向的共价药物发现.
- 为了解决数据完整性和同时测量ABPP中的蛋白质变化的局限性.
主要方法:
- 开发了用于活细胞化学蛋白组学的CysDig平台.
- 选了288个氨酸反应电友与300个注释的氨酸位点.
- 利用质谱法进行全蛋白质组的量化.
主要成果:
- 确定了向多个氨酸位点的共价结合剂.
- 观察到ACAT1.1的急性化合物诱导蛋白质降解.
- 验证了一种涉及HUWE1的分子,显示化学抑制稳定基质.
结论:
- CysDig是一个强大的,有针对性的平台,用于活细胞共价药物查.
- 该平台扩展了活细胞中联体发现的方法.
- 在识别共价结合剂和蛋白质降解效应方面已证明有用.
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