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引用次数: 0
摘要
靶向蛋白降解(TPD)是指利用由靶蛋白和泛素连接酶(E3)配体组成的蛋白水解靶向嵌合体(PROTACs),将泛素-蛋白酶体系统(UPS)重新定向到靶蛋白上。然而,尽管E3连接酶的数量众多,但PROTACs中使用的E3配体仍然有限。在这里,我们报告发现了一种以苯丙酸为骨架的小分子降解子,它来自于 E3 连接酶 S 期激酶相互作用蛋白 2(Skp2)的已知配体。我们利用这种降解子设计了诱导融合了HaloTag的蛋白质蛋白酶体降解的PROTACs,并确定了关键的结构关系。令人惊讶的是,我们的机理研究排除了 Skp2 的参与,这表明该降解子在 UPS 中招募了其他蛋白。
A small-molecule degron with a phenylpropionic acid scaffold
Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to redirect the ubiquitin–proteasome system (UPS) to the target protein, has emerged as a promising strategy in drug discovery. However, despite the vast number of E3 ligases, the repertoire of E3 ligands utilized in PROTACs remains limited. Here, we report the discovery of a small-molecule degron with a phenylpropionic acid skeleton, derived from a known ligand of S-phase kinase-interacting protein 2 (Skp2), an E3 ligase. We used this degron to design PROTACs inducing proteasomal degradation of HaloTag-fused proteins, and identified key structural relationships. Surprisingly, our mechanistic studies excluded the involvement of Skp2, suggesting that this degron recruits other protein(s) within the UPS.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.