模块化乙烯基胺酸用于氨酸导向蛋白向
Christian E Stieger1,2, Charlotte Völkel1,3, Mathias B Bertelsen1
1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
Journal of the American Chemical Society
|February 10, 2026
概括
乙烯基胺酸 (VPAs) 是一种新型的氨酸电友,为共价抑制剂的发展提供了更好的选择性. 这些化合物显示出减少的目标外效应,并通过PROTACs实现向蛋白质降解.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
背景情况:
- 向氨酸残留物的共价抑制剂在药物发现和蛋白质组学中至关重要.
- 现有的电友,如乙胺和烯胺,在选择性上有局限性.
研究的目的:
- 引入乙烯基胺酸 (VPAs) 作为一种新的选择性氨酸电友类.
- 评估VPA的反应性,选择性和在开发共价抑制剂和PROTACs中的实用性.
主要方法:
- 评估了与谷氨和人类细胞溶解酸中的VPA反应性.
- 开发了VPA功能化的阿法替尼和易布鲁替尼衍生物.
- 使用基于凝和基于质谱的基于活动的蛋白质分析 (ABPP).
- 构建了一个基于VPA的蛋白质分解向化马体 (PROTAC).
主要成果:
- 与传统的电友相比,VPA的内在反应性较低.
- VPA衍生品显示出有限的非特异性反应性和减少的目标外接触.
- 具有VPA功能的药物保持了抑制剂的有效性.
- 基于VPA的PROTAC已成功开发用于向蛋白质降解.
结论:
- VPAs代表了一种选择性和模块化电类,用于氨酸导向的共价变异.
- VPA扩大了开发具有有利反应性概况的共价抑制剂的化学空间.
- 通过PROTAC开发,VPAs促进了针对性的蛋白质降解策略.
相关概念视频
Directing Proteins to the Rough Endoplasmic Reticulum
17.9K
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
17.9K
Protein-protein Interfaces
14.8K
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...
14.8K
Protein and Protein Structure
88.9K
Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
A protein's shape is critical to its function. For example, an enzyme...
A protein's shape is critical to its function. For example, an enzyme...
88.9K
Protein Folding
128.2K
Overview
128.2K
Directing Effect of Substituents: meta-Directing Groups
6.0K
Substituents on the benzene ring that direct an incoming electrophile to undergo substitution at the meta position are called meta directors. All meta directors either have a positive charge on the atom directly bonded to the ring or a partial positive charge. These groups function by withdrawing electrons from the ring through inductive and resonance effects. Consider the carbocation intermediates formed upon the addition of an electrophile on nitrobenzene at the...
6.0K
Covalently Linked Protein Regulators
9.7K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.7K


