Rosenbaum Mette Ishøy, Clemmensen Louise S, Bredt David S, Bettler Bernhard, Strømgaard Kristian
Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
Nat Rev Drug Discov. 2020 Dec;19(12):884-901. doi: 10.1038/s41573-020-0086-4. Epub 2020 Nov 11.
Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach - targeting receptor complexes - is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein-protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research.
靶向受体蛋白，如配体门控离子通道和G蛋白偶联受体，直接促成了大多数用于调节受体信号传导的药物的发现。然而，随着对新型和改良药物的探索不断继续，一种创新方法——靶向受体复合物——正在兴起。受体复合物由核心受体蛋白和受体相关蛋白组成，这些蛋白对受体的整体结构、功能和定位有深远影响。因此，靶向受体复合物内的关键蛋白质-蛋白质相互作用为开发副作用更少的更具选择性的药物提供了机会。在本综述中，我们讨论了我们目前对配体门控离子通道和G蛋白偶联受体复合物的理解，并讨论了对其进行药理学调节的策略。尽管对于大多数受体复合物来说，此类策略仍处于临床前开发阶段，但它们例证了如何对受体复合物进行药物作用，并为这个新兴的研究领域奠定了基础。
