ArticleBiochemical pharmacology2017
Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1.
Article in Biochemical pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 59 citations in OpenAlex.
- Review
- Discovery of Biased Dual-Agonists of Glucagon-Like Peptide 1 and Glucagon Receptors through Mutation of a Conserved Aspartate.ACS medicinal chemistry letters · 2026Article
- Structural basis of PTH1R-β-arrestin core engagement reveals design principles for G-protein-biased therapeutics.Nature structural & molecular biology · 2026Article
- Co-Translational Incorporation ofJournal of the American Chemical Society · 2026Article
- Agonism and Biased Signaling.Handbook of experimental pharmacology · 2026Review
- Peptide-based therapeutics targeting GPCRs: recent applications in the treatment of metabolic disorders.Frontiers in pharmacology · 2026Review
- Prolonged signaling of backbone-modified glucagon-like peptide-Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Phosphorylation Sites of the Gastric Inhibitory Polypeptide Receptor (GIPR) Revealed by Trapped-Ion-Mobility Spectrometry Coupled to Time-of-Flight Mass Spectrometry (TIMS-TOF MS).Journal of the American Chemical Society · 2023Article
- Effects of Replacing a Central Glycine Residue in GLP-1 on Receptor Affinity and Signaling Profile.Chembiochem : a European journal of chemical biology · 2023Article
- Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.The Journal of clinical endocrinology and metabolism · 2023Article
- Structure and Molecular Mechanism of Signaling for the Glucagon-like Peptide-1 Receptor Bound to Gs Protein and Exendin-P5 Biased Agonist.Journal of the American Chemical Society · 2023Article
- Hormone Analogues with Unique Signaling Profiles from Replacement of α-Residue Triads with β/γ Diads.Journal of the American Chemical Society · 2023Article
- Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Understanding VPAC receptor family peptide binding and selectivity.Nature communications · 2022Article
- The therapeutic potential of GLP-1 receptor biased agonism.British journal of pharmacology · 2022 · on this mapReview
- Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation.Nature communications · 2022Article
- ACTH(6-9)PGP Peptide Protects SH-SY5Y Cells from HMolecules (Basel, Switzerland) · 2021Article
- GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats.ACS pharmacology & translational science · 2021Article
- GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists.The Journal of clinical endocrinology and metabolism · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for the treatment of type 2 diabetes. Activation of this receptor promotes insulin secretion and blood glucose regulation. The GLP-1R can initiate signaling through several intracellular pathways upon activation by GLP-1. GLP-1R ligands that preferentially stimulate subsets among the natural signaling pathways ("biased agonists") could be useful as tools for elucidating the consequences of specific pathways and might engender therapeutic agents with tailored effects. Using HEK-293 cells recombinantly expressing human GLP-1R, we have previously reported that backbone modification of GLP-1, via replacement of selected α-amino acid residues with β-amino acid residues, generates GLP-1 analogues with distinctive preferences for promoting G protein activation versus β-arrestin recruitment. Here, we have explored the influence of cell background across these two parameters and expanded our analysis to include affinity and other key signaling pathways (intracellular calcium mobilization and ERK phosphorylation) using recombinant human GLP-1R expressed in a CHO cell background, which has been used extensively to demonstrate biased agonism of GLP-1R ligands. The new data indicate that α/β-peptide analogues of GLP-1 exhibit a range of distinct bias profiles relative to GLP-1 and that broad assessment of signaling endpoints is required to reveal the spectrum of behavior of modified peptides. These results support the view that backbone modification via α→β amino acid replacement can enable rapid discovery of peptide hormone analogues that display substantial signal bias at a cognate GPCR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.