整个蛋白质组的数据指导了利用DNA编码的化学库发现素向的共价抑制剂
Xinyuan Wu1,2, Shunyao Li3, Ting Liang4,5
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Angewandte Chemie (International ed. in English)
|April 14, 2025
概括
这项研究引入了一种使用共价DNA编码化学库 (CoDEL) 和基于活性的蛋白质分析 (ABPP) 来发现用于药物开发的素向共价抑制剂的新方法.
科学领域:
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
- 蛋白质组学是指蛋白质组学.
背景情况:
- 性抑制剂传统上向氨酸残留物.
- 将共价抑制剂的发现扩展到其他核性残留物,如氨酸至关重要.
- 共价DNA编码化学库 (CoDEL) 为药物发现提供了一个强大的平台.
研究的目的:
- 开发和应用Codel技术,用于识别氨酸向性共价抑制剂.
- 为了利用全蛋白质组基于活动的蛋白质分析 (ABPP) 数据进行目标识别.
- 探索氨酸修饰的多种共价反应机制.
主要方法:
- 利用一个拥有1070万成员的Codel库,使用素反应弹头.
- 整合全蛋白质组的ABPP数据,以评估氨酸的分布和结合性.
- 采用由ABPP数据指导的Codel选择来识别潜在的抑制剂.
- 进行了抑制剂结合和作用机制的深入表征.
主要成果:
- 鉴定了潜在的素向糖酸突变酶1 (PGAM1),代蛋白 (BRD) 蛋白和无素结合酶E2N (UBE2N) 的潜在素向共价抑制剂.
- 发现了利用光共价,可逆共价和不可逆共价机制的抑制剂.
- 通过不可逆转的共价抑制剂调节蛋白质复合体构造,阐明了一种通过不可逆转的共价抑制剂调节UBE2N的新机制.
结论:
- ABPP-CoDEL战略提供了一种高效和多功能方法,用于发现向功能性溶酶的共价抑制剂.
- 这项工作扩大了共价药物发现的范围,超出了氨酸残留物.
- 已识别的抑制剂和机制为治疗干预提供了新的途径.
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