Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics

Abstract

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.