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

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 <i>in vivo</i>. 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</i>, <i>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 <i>in vivo</i>. Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.