Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors

Yuliantie, Elita; Darbalaei, Sanaz; Dai, Antao; Zhao, Peishen; Yang, Dehua; Sexton, Patrick M.; Wang, Mingwei; Wootten, Denise

doi:10.1016/j.bcp.2020.114001

Cited by 43 publications

(30 citation statements)

References 51 publications

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“…To exclude possible anomalous pharmacology by the artificial nature of the complementation assay, additional independent techniques were used and showed an equivalent pharmacological profile for tirzepatide recruitment of ARRB1 and ARRB2 at both the human and mouse GLP-1R ( Supplemental Figure 2 ). These findings are generally consistent with results recently reported by Yuliantie et al ( 24 ). In our studies, despite exhibiting low efficacy, the relative potency of tirzepatide for arrestin recruitment correlates well with binding affinity ( Supplemental Table 1 ).…”

Section: Resultssupporting

confidence: 94%

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Willard¹,

Douros²,

Gabe³

et al. 2020

JCI Insight

260

192

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Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

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Section: Resultssupporting

confidence: 94%

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Willard¹,

Douros²,

Gabe³

et al. 2020

JCI Insight

260

192

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“…Whilst GLP-1R agonists developed specifically to G protein-directed signalling are yet to be tested in humans, the potential utility of this approach is supported by the recent observation that Tirzepatide, a dual GLP-1R/GIPR agonist peptide currently in late stage clinical trials (18), and its non-acylated precursor show a significant degree of bias at the GLP-1R in favour of cAMP over β-arrestin recruitment (19,73). Conflicting reports exist for bias between cAMP and βarrestin recruitment to the GIPR for Tirzepatide, with one study showing bias in favour of cAMP and another showing no difference (19,74). Biased agonism at the GCGR is relatively unexplored, except for a recent study of a series of dual GLP-1R/GCGR agonists in which small response amplitude for β-arrestin-2 recruitment to GCGR hampered bias assessments (75), but should be further explored in the future.…”

Section: Discussionmentioning

confidence: 99%

Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors

Jones

McGlone

Fang

et al. 2021

Journal of Biological Chemistry

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Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitisation and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signalling was increased in response to the endogenous ligand for each receptor. Moreover, in wild-type cells, “biased” GLP-1, GCG and GIP analogues with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogues increased the duration of cAMP signalling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for development of GLP-1R, GIPR and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

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“…Both also showed significantly reduced recruitment of β -arrestin-2 to GCGR compared to glucagon, a difference that was larger than the GCGR efficacy reduction seen with SRB103Q compared to SRB103H. Thus, cotadutide and SAR425899 may well be additional examples of incretin receptor ligands retrospectively identified as showing biased agonist properties, as was recently found for the dual GLP-1R/GIPR agonist tirzepatide [71,72]. On the other hand, the recorded cAMP potencies for cotadutide and SAR425899 in the study of Darbalaei et al relative to the endogenous comparator ligands are orders of magnitude less than reported previously [70,73], raising the possibility that the cellular systems used to evaluate the pharmacology of these ligands could have affected the results.…”

Section: Improved Anti-hyperglycaemic Efficacy Of Srb103q Is Preserved With Chronic Administrationmentioning

confidence: 73%

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

Pickford¹,

Lucey²,

Rujan³

et al. 2021

Preprint

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Objective: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein activation and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. Methods: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss. Results: Ligand-specific reductions in β-arrestin-2 recruitment led to reduced GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. Conclusions: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

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Pharmacological characterization of mono-, dual- and tri-peptidic agonists at GIP and GLP-1 receptors

Cited by 43 publications

References 51 publications

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

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