Abolishing β-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists
Author(s)
Type
Journal Article
Abstract
Aim
Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.
Materials and Methods
New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.
Results
First, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics.
Conclusions
Completely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.
Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.
Materials and Methods
New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.
Results
First, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics.
Conclusions
Completely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.
Date Issued
2024-01
Date Acceptance
2023-08-28
Citation
Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, 2024, 26 (1), pp.65-77
ISSN
1462-8902
Publisher
Wiley
Start Page
65
End Page
77
Journal / Book Title
Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics
Volume
26
Issue
1
Copyright Statement
© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:001075497900001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
antidiabetic drug
antiobesity drug
CAMP
DISCOVERY
Endocrinology & Metabolism
GLP-1 analogue
GLP-1 RECEPTOR
GLUCOSE
Life Sciences & Biomedicine
LIRAGLUTIDE
OBESITY
OPEN-LABEL
pharmacology
Science & Technology
SELECTIVITY
SEMAGLUTIDE
WEIGHT
Publication Status
Published
Date Publish Online
2023-10-05