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GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats.
- Source :
-
ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2021 Jan 19; Vol. 4 (1), pp. 296-313. Date of Electronic Publication: 2021 Jan 19 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH <subscript>2</subscript> (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2021 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 2575-9108
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- ACS pharmacology & translational science
- Publication Type :
- Academic Journal
- Accession number :
- 33615180
- Full Text :
- https://doi.org/10.1021/acsptsci.0c00193