Tasma Zoe, Garelja Michael L, Jamaluddin Aqfan, Alexander Tyla I, Rees Tayla A
Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand.
Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK.
Pharmacol Ther. 2025 Jun;270:108846. doi: 10.1016/j.pharmthera.2025.108846. Epub 2025 Apr 9.
Class B G protein-coupled receptors (GPCRs) are a subfamily of 15 peptide hormone receptors with diverse roles in physiological functions and disease pathogenesis. Over the past decade, several novel therapeutics targeting these receptors have been approved for conditions like migraine, diabetes, and obesity, many of which are ground-breaking and first-in-class. Most of these therapeutics are agonist analogues with modified endogenous peptide sequences to enhance receptor activation or stability. Several small molecule and monoclonal antibody antagonists have also been approved or are in late-stage development. Differences in the sequence and structure of these therapeutic ligands lead to distinct signalling profiles, including biased behaviour or inhibition of specific pathways. Understanding this biased pharmacology offers unique development opportunities for improving therapeutic efficacy and reducing adverse effects. This review summarises current knowledge on the ligand bias of approved class B GPCR drugs, highlights strategies to refine and exploit their pharmacological profiles, and discusses key considerations related to receptor structure, localisation, and regulation for developing new therapies.
B类G蛋白偶联受体（GPCRs）是一个由15种肽激素受体组成的亚家族，在生理功能和疾病发病机制中发挥着多种作用。在过去十年中，几种针对这些受体的新型疗法已被批准用于治疗偏头痛、糖尿病和肥胖症等疾病，其中许多都是开创性的和同类首创的。这些疗法大多是激动剂类似物，其内源肽序列经过修饰，以增强受体激活或稳定性。几种小分子和单克隆抗体拮抗剂也已被批准或正处于后期开发阶段。这些治疗性配体在序列和结构上的差异导致了不同的信号传导模式，包括偏向性作用或对特定途径的抑制。了解这种偏向性药理学为提高治疗效果和减少不良反应提供了独特的开发机会。本综述总结了目前关于已批准的B类GPCR药物配体偏向性的知识，强调了优化和利用其药理学特征的策略，并讨论了与受体结构、定位和调节相关的关键考虑因素，以开发新的疗法。
