Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
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Supplementary information
Published version
Author(s)
Type
Journal Article
Abstract
Objective
The objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression.
Methods
In vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice.
Results
A C-terminally acylated ligand, [F1,K⁴⁰.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,K⁴⁰.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.
Conclusions
C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
The objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression.
Methods
In vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice.
Results
A C-terminally acylated ligand, [F1,K⁴⁰.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,K⁴⁰.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.
Conclusions
C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
Date Issued
2020-07-01
Date Acceptance
2020-04-02
Citation
Molecular Metabolism, 2020, 37
ISSN
2212-8778
Publisher
Elsevier
Journal / Book Title
Molecular Metabolism
Volume
37
Copyright Statement
© 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor
Medical Research Council (MRC)
The Academy of Medical Sciences
Society for Endocrinology
European Foundation for the Study of Diabetes
Grant Number
MR/R010676/1
N/A
N/A
98102
Subjects
Biased signalling
Exendin-4
Glucagon-like peptide-1 receptor
Trafficking
Type 2 diabetes
0601 Biochemistry and Cell Biology
0606 Physiology
Publication Status
Published
Article Number
ARTN 100991
Date Publish Online
2020-04-08