We are now in the middle of a so-called “fourth wave” of drug innovation: multispecific medicines aimed at diseases and targets previously thought to be “undruggable”; by inducing proximity between two or more proteins, for example, a target and an effector that do not naturally interact, such modalities have potential far beyond the scope of conventional drugs. In particular, targeted protein degradation (TPD) strategies to destroy disease-associated proteins have emerged as an exciting pipeline in drug discovery. Most efforts are focused on intracellular proteins, whereas membrane proteins have been less thoroughly explored despite the fact that they comprise roughly a quarter of the human proteome with G-protein coupled receptors (GPCRs) notably dysregulated in many diseases. Here, we discuss the opportunities and challenges of developing degraders for membrane proteins with a focus on GPCRs. We provide an overview of different TPD platforms in the context of membrane-tethered targets, and we present recent degradation technologies highlighting their potential application to GPCRs.

中文翻译：

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如何靶向膜蛋白进行降解：将 GPCR 带入 TPD 折叠


我们现在正处于所谓的“第四次药物创新浪潮”中：针对以前被认为“不可成药”的疾病和靶点的多特异性药物;通过诱导两种或多种蛋白质之间的接近，例如，不自然相互作用的靶标和效应子，这种方式具有远远超出常规药物范围的潜力。特别是，破坏疾病相关蛋白的靶向蛋白质降解 （TPD） 策略已成为药物发现中令人兴奋的管道。大多数工作都集中在细胞内蛋白上，而膜蛋白则鲜为人知，尽管它们约占人类蛋白质组的四分之一，并且 G 蛋白偶联受体 （GPCR） 在许多疾病中明显失调。在这里，我们讨论了开发膜蛋白降解剂的机遇和挑战，重点是 GPCR。我们概述了膜栓系靶标背景下的不同 TPD 平台，并介绍了最近的降解技术，突出了它们在 GPCR 中的潜在应用。