用于全蛋白体连接体和目标发现的亚乙烯电:支持向蛋白质降解
Jiayi Du1,2,3, Shengrong Li4, Fang Xu1,2,3
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Journal of medicinal chemistry
|June 26, 2025
概括
研究人员开发了一种用于化学蛋白质学的新型终端乙烯反应弹头. 这种新方法扩大了目标发现,并使得创建新的小分子降解剂为向蛋白质降解.
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:
- 化学蛋白质学和共价探针对于识别药物标和用于向蛋白质降解的E3酶至关重要.
- 现有的电友探针有局限性,使得蛋白质组的很大一部分,包括E3连接酶,无法访问.
研究的目的:
- 开发一种新型的反应性弹头,以扩大化学蛋白质组学的范围.
- 为了使新的可药物向和E3结合酶的发现.
- 为有针对性的蛋白质降解设计先进的小分子降解剂.
主要方法:
- 开发一个终端亚乙烯反应弹头.
- 在细胞条件下通过脱来进行蛋白质形的战头的现场生成.
- 应用基于碎片的连接物发现 (FBLD) 来识别蛋白质标.
主要成果:
- 通过使用新弹头,成功攻击未经表征的目标和E3泛素酶.
- 证明了乙烯碎片与必需蛋白质的共价结合,包括TUFM的C130,可能调节蛋白质功能.
- 使用弹头设计了针对BRD4的小分子降解剂,有效降解BRD4而不产生效应.
结论:
- 终端乙烯弹头为蛋白质组概况和目标识别提供了一个新的平台.
- 这种方法有助于发现新型配体和开发下一代小分子降解剂.
- 这项研究扩大了化学蛋白质学在药物发现和向蛋白质降解方面的能力.
相关概念视频
Regulated Protein Degradation
7.7K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.7K
Ligand Binding Sites
13.5K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
13.5K
The Proteasome
1.2K
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
1.2K
Protein-protein Interfaces
13.7K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
13.7K


