4.7 Article

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

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 190, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114656

Keywords

GLP-1R; Biased agonism; Endocytosis; Exendin-4; beta-arrestin

Funding

  1. MRC [MR/R010676/1, MR/N00275X/1, MR/S025618/1, MR/R022259/1, MR/L02036X/1]
  2. BBSRC
  3. NIHR
  4. NIHR Biomedical Research Centre Funding Scheme
  5. Diabetes UK [17/0005681]
  6. Academy of Medical Sciences
  7. British Society for Neuroendocrinology
  8. European Federation for the Study of Diabetes
  9. EPSRC
  10. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [715884]
  11. Wellcome Trust [212625/Z/18/Z]
  12. EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY) [115881]
  13. Diabetes UK Harry Keen Fellowship
  14. Society for Endocrinology
  15. Medical Research Council [MR/N00275X/1, MR/S025618/1] Funding Source: researchfish

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In this study, differences between the GLP-1R agonists P5 and exendin-F1 were examined through various assays, revealing that while exendin-F1 showed lower acute efficacy, it demonstrated greater effects on insulin secretion and sustained anti-hyperglycaemic efficacy in mice compared to P5.
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 beta-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 beta-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs 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.

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