Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor

• Published in: ACS chemical biology 2020-06, Vol.15 (6), p.1340-1348
• Main Authors: Bird, Gregory H, Fu, Accalia, Escudero, Silvia, Godes, Marina, Opoku-Nsiah, Kwadwo, Wales, Thomas E, Cameron, Michael D, Engen, John R, Danial, Nika N, Walensky, Loren D
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Drug Discovery; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Humans; Male; Mice; Molecular Docking Simulation; Peptides - chemistry; Peptides - pharmacology
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.0c00308

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 . 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 , + 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 . Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.