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Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor
- Source :
- ACS Chem Biol
- Publication Year :
- 2020
-
Abstract
- Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. A primary challenge has been the naturally short half-life of GLP-1 due to its rapid proteolytic degradation in vivo. Whereas mutagenesis and lipidation strategies have yielded clinical agents, we developed an alternative approach to preserving the structure and function of GLP-1 by all-hydrocarbon i, i + 7 stitching. This particular "stitch" is especially well-suited for reinforcing and protecting the structural fidelity of GLP-1. Lead constructs demonstrate striking proteolytic stability and potent biological activity in vivo. Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.
- Subjects :
- 0301 basic medicine
Agonist
Male
endocrine system
medicine.drug_class
medicine.medical_treatment
Mutagenesis (molecular biology technique)
Lipid-anchored protein
Peptide
01 natural sciences
Biochemistry
Glucagon-Like Peptide-1 Receptor
Article
Cell Line
03 medical and health sciences
Mice
In vivo
Glucagon-Like Peptide 1
Drug Discovery
medicine
Animals
Humans
Receptor
chemistry.chemical_classification
010405 organic chemistry
Chemistry
Insulin
digestive, oral, and skin physiology
Biological activity
General Medicine
0104 chemical sciences
Cell biology
Molecular Docking Simulation
030104 developmental biology
Molecular Medicine
Peptides
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 15548937
- Volume :
- 15
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- ACS chemical biology
- Accession number :
- edsair.doi.dedup.....8efc978f89188983f56eeca10622b09c