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Molecular Pharmacology

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Acylation of the incretin peptide exendin-4 directly impacts GLP-1 receptor signalling and trafficking

Maria Lucey, Tanyel Ashik, Amaara Marzook, Yifan Wang, Joelle Goulding, Atsuro Oishi, Johannes Broichhagen, David J Hodson, James Minnion, Yuval Elani, Ralf Jockers, Steven J Briddon, Stephen R Bloom, Alejandra Tomas and Ben Jones
Molecular Pharmacology July 27, 2021, MOLPHARM-AR-2021-000270; DOI: https://doi.org/10.1124/molpharm.121.000270
Maria Lucey
1Imperial College London, United Kingdom
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Tanyel Ashik
1Imperial College London, United Kingdom
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Amaara Marzook
1Imperial College London, United Kingdom
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Yifan Wang
1Imperial College London, United Kingdom
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Joelle Goulding
2University of Nottingham, United Kingdom
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Atsuro Oishi
3Inserm, France
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Johannes Broichhagen
4Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
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David J Hodson
5University of Birmingham, United Kingdom
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James Minnion
1Imperial College London, United Kingdom
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Yuval Elani
1Imperial College London, United Kingdom
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Ralf Jockers
3Inserm, France
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Steven J Briddon
2University of Nottingham, United Kingdom
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Stephen R Bloom
1Imperial College London, United Kingdom
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Alejandra Tomas
1Imperial College London, United Kingdom
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  • For correspondence: ben.jones@imperial.ac.uk
Ben Jones
1Imperial College London, United Kingdom
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  • ORCID record for Ben Jones
  • For correspondence: ben.jones@imperial.ac.uk
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Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitisation and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cyclic adenosine monophosphate (cAMP). Here we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analogue, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and β-arrestins, endocytic and post-endocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency but exendin-4-C16 showed ~2.5-fold bias towards G protein recruitment and a ~60% reduction in β-arrestin-2 recruitment efficacy compared to exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting towards recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach, and a ~70% increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology.

Significance Statement Acylation is a common strategy to enhance the pharmacokinetics of peptide-based drugs. Our work shows how acylation can also affect various other pharmacological parameters, including biased agonism, receptor trafficking and interactions with the plasma membrane, which may be therapeutically important.

  • Biased agonism
  • G protein coupled signaling
  • g protein-coupled receptors (GPCRS)
  • GLP1
  • receptor trafficking
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Pharmacology of acylated exendin-4

Maria Lucey, Tanyel Ashik, Amaara Marzook, Yifan Wang, Joelle Goulding, Atsuro Oishi, Johannes Broichhagen, David J Hodson, James Minnion, Yuval Elani, Ralf Jockers, Steven J Briddon, Stephen R Bloom, Alejandra Tomas and Ben Jones
Molecular Pharmacology July 27, 2021, MOLPHARM-AR-2021-000270; DOI: https://doi.org/10.1124/molpharm.121.000270

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OtherArticle

Pharmacology of acylated exendin-4

Maria Lucey, Tanyel Ashik, Amaara Marzook, Yifan Wang, Joelle Goulding, Atsuro Oishi, Johannes Broichhagen, David J Hodson, James Minnion, Yuval Elani, Ralf Jockers, Steven J Briddon, Stephen R Bloom, Alejandra Tomas and Ben Jones
Molecular Pharmacology July 27, 2021, MOLPHARM-AR-2021-000270; DOI: https://doi.org/10.1124/molpharm.121.000270
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