Imperial College London
Alternate

ProfessorGuyRutter

Faculty of Medicine, Department of Medicine

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3340g.rutter Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Jones:2020:10.1016/j.molmet.2020.100991,
author = {Jones, B and Pickford, P and Lucey, M and Tomas-Catala, A and Minnion, J and Bitsi, S and Ungewiss, J and Schoeneberg, K and Rutter, G and Bloom, S},
doi = {10.1016/j.molmet.2020.100991},
journal = {Molecular Metabolism},
title = {Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists},
url = {http://dx.doi.org/10.1016/j.molmet.2020.100991},
volume = {37},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ObjectiveThe 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.MethodsIn 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.ResultsA C-terminally acylated ligand, [F1,K.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,K.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
AU  - Jones,B
AU  - Pickford,P
AU  - Lucey,M
AU  - Tomas-Catala,A
AU  - Minnion,J
AU  - Bitsi,S
AU  - Ungewiss,J
AU  - Schoeneberg,K
AU  - Rutter,G
AU  - Bloom,S
DO  - 10.1016/j.molmet.2020.100991
PY  - 2020///
SN  - 2212-8778
TI  - Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
T2  - Molecular Metabolism
UR  - http://dx.doi.org/10.1016/j.molmet.2020.100991
UR  - http://hdl.handle.net/10044/1/79132
VL  - 37
ER  -
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