Biased agonism is a phenomenon where different ligands acting on the same receptor trigger distinct signaling pathways, leading to varied biological outcomes [1]. This concept is gaining significant attention in drug discovery, especially in the context of G protein-coupled receptors (GPCRs) like the glucagon-like peptide-1 receptor (GLP-1R). The GLP-1R, a class B1 GPCR, is integral to metabolic regulation, particularly in glucose homeostasis and insulin secretion, making it a well-established target for treating type 2 diabetes and obesity [2]. It is primarily coupled to the Gs protein, which leads to the production of cyclic AMP (cAMP). However, GLP-1R can also engage other G proteins, such as Gi/o and Gq/11, leading to different downstream effects, such as inhibition of cAMP production or mobilization of intracellular calcium, respectively [3]. Additionally, GLP-1R couple to G protein-coupled receptor kinases (GRKs) and recruit β-arrestins, adding another layer of complexity to its signaling [4].
Biased agonism at the GLP-1R has been extensively studied, revealing that different ligands can stabilize distinct receptor conformations, leading to diverse signaling outcomes. Compared to the endogenous ligand GLP-1, another endogenous ligand, oxyntomodulin, exhibits a bias towards extracellular signal-regulated kinase (ERK) phosphorylation [5]. In contrast, exendin-P5, another GLP-1R agonist, is biased towards cAMP accumulation but with reduced β-arrestin recruitment, relative to GLP-1 [6]. These differences in signaling profiles can have significant physiological implications. For example, in vivo studies in diabetic models have shown that although exendin-P5 induces lower insulin release compared to exendin, both ligands exhibit similar efficacy in lowering blood glucose levels. Moreover, exendin-P5 has been observed to reduce adipose tissue size more effectively than exendin, suggesting that biased agonism can lead to distinct therapeutic outcomes.
The molecular mechanisms underlying biased agonism at the GLP-1R are beginning to be elucidated through a combination of mutagenesis, pharmacological studies, and structural analysis. Research by Prof. Denise Wootten and colleagues has highlighted the importance of extracellular loop 2 (ECL2) in stabilizing the receptor conformation necessary for Gs protein recruitment and cAMP production [5]. In contrast, ligands like oxyntomodulin that preferentially activate ERK1/2 signaling interact more significantly with extracellular loop 3 (ECL3). Cryo-electron microscopy (cryo-EM) structures of GLP-1R bound to different agonists have provided further insights into how specific regions of the receptor contribute to biased signaling. For instance, the interaction of GLP-1 with ECL3, which leads to a tight conformation of the receptor's transmembrane domain (TM), contrasts with the looser interaction seen with biased agonists like exendin-P5, peptide-19, CHU-138 and TT-OAD2 [7]. These agonists exhibit less interaction with ECL3, resulting in an open conformation of the TM6-ECL3-TM7 axis, which is associated with their bias towards cAMP production and reduced β-arrestin recruitment.
The concept of biased agonism has been effectively leveraged in drug discovery, as demonstrated by the development of tirzepatide, a GLP-1R/GIPR dual agonist. Tirzepatide's success underscores the potential of designing drugs that selectively target beneficial signaling pathways. Tirzepatide’s superior effect over semaglutide has been attributed in part to biased agonism at the GLP-1R. Tirzepatide is a full agonist for cAMP production at the GLP-1R which minimal ability to recruit β-arrestins, relative to GLP-1 [8-10].
In conclusion, biased agonism at the GLP-1R represents a promising strategy for optimizing therapeutic outcomes in metabolic diseases. By selectively targeting specific signaling pathways, it is possible to develop drugs with improved efficacy, as exemplified by tirzepatide. As our understanding of the molecular basis of biased agonism continues to grow, it is likely to play an increasingly important role in the design of next-generation therapeutics. Indeed, incretin-based drugs like Novo Nordisk's Wegovy and Eli Lilly's Zepbound are advancing diabetes and obesity management, driving the obesity market toward $66 billion by 2030 and on track to become one of the most lucrative drug classes, potentially reaching $100-200 billion in annual sales [11].
References
1. Kenakin, T. and A. Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov, 2013. 12(3): p. 205-16.
2. Drucker, D.J., Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab, 2018. 27(4): p. 740-756.
3. AZIETAKU, J.T., Profiling Glucagon-Like Peptide -1 Receptor Transducer Coupling, Signalling and Biased Agonism. 2023, Monash University.
4. McNeill, S.M., et al., The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation. Biochemical Pharmacology, 2024. 222: p. 116119.
5. Wootten, D., et al., The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism. Cell, 2016. 165(7): p. 1632-1643.
6. Zhang, H., et al., Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects. Nat Commun, 2015. 6: p. 8918.
7. Cary, B.P., et al., New Insights into the Structure and Function of Class B1 GPCRs. Endocr Rev, 2023. 44(3): p. 492-517.
8. Willard, F.S., et al., Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight, 2020. 5(17).
9. Anson, M., et al., Incidence of new onset type 2 diabetes in adults living with obesity treated with tirzepatide or semaglutide: real world evidence from an international retrospective cohort study. eClinicalMedicine, 2024. 75.
10. Rodriguez, P.J., et al., Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. JAMA Internal Medicine, 2024. 184(9): p. 1056-1064.
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