Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1

Amaara Marzook, Shiqian Chen, Philip Pickford, Maria A. Lucey, Yifan Wang, Ivan R Corrêa, Johannes Broichhagen, David Hodson, Victoria Salem, Guy A Rutter, Tricia M. Tan, Stephen R. Bloom, Alejandra Tomas, Ben Jones

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The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-G complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.
Original languageEnglish
Article number114656
Number of pages12
JournalBiochemical Pharmacology
Early online date12 Jun 2021
Publication statusPublished - Aug 2021

Bibliographical note

Funding Information:
The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the funders. This project was supported by an MRC project grant (MR/R010676/1) to A.T. B.J. S.R.B. and G.A.R. The European Federation for the Study of Diabetes has supported B.J. and A.T. in this work. A.T. also acknowledges funding from Diabetes UK. B.J. acknowledges support from the Academy of Medical Sciences, Society for Endocrinology, The British Society for Neuroendocrinology, the European Federation for the Study of Diabetes, and an EPSRC capital award. D.J.H. was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). G.A.R. was supported by Wellcome Trust Investigator (212625/Z/18/Z) Awards, MRC Programme (MR/R022259/1) and Experimental Challenge Grant (DIVA, MR/L02036X/1), and Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) grants. This work has received support from the EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY grant No 115881) to G.A.R. V.S. was supported by a Diabetes UK Harry Keen Fellowship. G.A.R., A.T. and B.J. have received grant funding from Sun Pharmaceuticals.

Publisher Copyright:
© 2021 The Authors


  • GLP-1R
  • biased agonism
  • endocytosis
  • exendin-4
  • β-arrestin


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