Tags

Type your tag names separated by a space and hit enter

Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1.
Biochem Pharmacol. 2017 07 15; 136:99-108.BP

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.

Authors+Show Affiliations

Department of Chemistry, University of Wisconsin, Madison, WI, United States.Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Australia.Department of Chemistry, University of Wisconsin, Madison, WI, United States.Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Australia.Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Australia. Electronic address: denise.wootten@monash.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28363772

Citation

Hager, Marlies V., et al. "Characterization of Signal Bias at the GLP-1 Receptor Induced By Backbone Modification of GLP-1." Biochemical Pharmacology, vol. 136, 2017, pp. 99-108.
Hager MV, Clydesdale L, Gellman SH, et al. Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. Biochem Pharmacol. 2017;136:99-108.
Hager, M. V., Clydesdale, L., Gellman, S. H., Sexton, P. M., & Wootten, D. (2017). Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. Biochemical Pharmacology, 136, 99-108. https://doi.org/10.1016/j.bcp.2017.03.018
Hager MV, et al. Characterization of Signal Bias at the GLP-1 Receptor Induced By Backbone Modification of GLP-1. Biochem Pharmacol. 2017 07 15;136:99-108. PubMed PMID: 28363772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. AU - Hager,Marlies V, AU - Clydesdale,Lachlan, AU - Gellman,Samuel H, AU - Sexton,Patrick M, AU - Wootten,Denise, Y1 - 2017/03/29/ PY - 2017/02/04/received PY - 2017/03/27/accepted PY - 2017/4/2/pubmed PY - 2017/6/14/medline PY - 2017/4/2/entrez KW - Biased agonism KW - Cell signaling KW - G protein coupled receptor KW - Glucagon-like peptide-1 receptor KW - Peptides SP - 99 EP - 108 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 136 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/28363772/Characterization_of_signal_bias_at_the_GLP_1_receptor_induced_by_backbone_modification_of_GLP_1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(17)30165-X DB - PRIME DP - Unbound Medicine ER -