The GLP-1R as a model for understanding and exploiting biased agonism in next generation medicines.

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) emerged as a pharmacologic target in cardiometabolic disease including diabetes and obesity over 30 years ago. The subsequent widespread clinical use of GLP-1R agonists including exenatide, liraglutide, and semaglutide has made the GLP-1R a preeminent model for understanding basic GPCR biology including the emergent field of biased agonism. Recent data demonstrate that the dual GLP-1R/glucose dependent insulinotropic polypeptide receptor (GIPR) agonist tirzepatide exhibits a biased signaling profile characterized by preferential Gαs activation over β-arrestin recruitment, which appears to contribute to its insulinotropic and body-weight reducing effects in preclinical models. This constitutes a major finding in which nuanced, mechanistic receptor signaling dynamics in vitro mediate real world clinical differentiation within a drug class. Because of the striking bench-top to bed side relevance of this biased signaling phenomenon we have undertaken a review of the emerging data detailing biased agonism at the GLP-1R. In this review we introduce the core concept of biased agonism followed by a detailed consideration of the key mechanisms including ligand-mediated bias, receptor mediated bias, and systems/cell-type bias. Current industry programs are largely, if not entirely, focused developing biased ligands and so we have dedicated a section of the review to a brief meta-analysis of compounds reported to drive biased signaling with a consideration of the structural determerminants of receptor:ligand interactions. In this work we aim to assess the current knowledge regarding signaling bias at the GLP-1R and how these ideas might be leveraged in future optimization.