Reversible Assembly of Proteolysis Targeting Chimeras.
Reversible Assembly of Proteolysis Targeting Chimeras.
复制标题
靶向嵌合体的蛋白水解的可逆组装。
DOI：
10.1021/acschembio.3c00199
复制
发表时间：
2023
影响因子：
4
通讯作者：
Kodadek,Thomas
中科院分区：
文献类型：
--
作者：
Gui,Weijun;Giardina,SarahF;Balzarini,Madeline;Barany,Francis;Kodadek,Thomas
蛋白水解靶向嵌合体（PROTAC）对于探针分子和药物先导物的开发具有重要的当前兴趣。然而，它们受到某些限制。PROTAC是具有次优细胞渗透性、溶解性和其他药物样性质的破坏规则的分子。特别是，它们表现出不寻常的剂量-反应曲线，其中高浓度的二价分子抑制降解活性，这种现象称为钩状效应。这可能会使其在体内的使用复杂化。在这项研究中，我们探索了一种新的方法来创建PROTAC，不表现出钩状效应。这是通过使靶蛋白和E3泛素连接酶配体具有在细胞中进行快速和可逆共价组装的功能来实现的。我们报道了自组装蛋白水解靶向嵌合体的发展，其介导Von Hippel-Lindau E3泛素连接酶的降解，并且没有表现出钩状效应。
PROteolysis TArgeting Chimeras (PROTACs) are of significant current interest for the development of probe molecules and drug leads. However, they suffer from certain limitations. PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In particular, they exhibit an unusual dose–response curve where high concentrations of the bivalent molecule inhibit degradation activity, a phenomenon known as the hook effect. This will likely complicate their use in vivo. In this study, we explore a novel approach to create PROTACs that do not exhibit a hook effect. This is achieved by equipping the target protein and E3 ubiquitin ligase ligands with functionalities that undergo rapid and reversible covalent assembly in cellulo. We report the development of Self-Assembled Proteolysis Targeting Chimeras that mediate the degradation of the Von Hippel–Lindau E3 ubiquitin ligase and do not evince a hook effect.