Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands; Department of Structural Biology and Biophysics, UCB Biopharma UK, Slough, UK.
Department of Structural Biology and Biophysics, UCB Biopharma UK, Slough, UK.
Curr Opin Chem Biol. 2022 Aug;69:102169. doi: 10.1016/j.cbpa.2022.102169. Epub 2022 Jun 21.
Targeting protein-protein interactions (PPIs) has become a common approach to tackle various diseases whose pathobiology is driven by their mis-regulation in important signalling pathways. Modulating PPIs has tremendous untapped therapeutic potential and different approaches can be used to modulate PPIs. Initially, therapeutic effects were mostly sought by inhibiting PPIs. However, by gaining insight in the mode of action of certain therapeutic compounds, it became clear that stabilising (i.e. enhancing) PPIs can also be useful. The latter strategy is recently gaining a lot of attention, as stabilising physiologic, or even inducing novel interactions of a target protein with E3 ubiquitin ligases forms the basis of the targeted protein degradation (TPD) approach. An emerging additional example for drug discovery based on PPI stabilisation are the 14-3-3 proteins, a family of regulatory proteins, which engages in many protein-protein interactions, some of which might become therapeutical targets.
靶向蛋白质-蛋白质相互作用（PPIs）已成为一种常见的方法，可用于解决多种疾病，这些疾病的病理生物学是由其在重要信号通路中的失调所驱动的。调节 PPI 具有巨大的未开发的治疗潜力，可以使用不同的方法来调节 PPI。最初，主要通过抑制 PPI 来寻求治疗效果。然而，通过深入了解某些治疗化合物的作用模式，人们清楚地认识到稳定（即增强）PPI 也可能是有用的。后一种策略最近受到了广泛关注，因为稳定生理相互作用，甚至诱导靶蛋白与 E3 泛素连接酶的新相互作用，构成了靶向蛋白降解（TPD）方法的基础。基于 PPI 稳定化的药物发现的一个新兴的额外例子是 14-3-3 蛋白，这是一类调节蛋白，参与许多蛋白质-蛋白质相互作用，其中一些可能成为治疗靶点。
