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A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Author:
Johnson, Lisa M., Barrick, Stacey, Hager, Marlies V., McFedries, Amanda, Homan, Edwin A., Rabaglia, Mary E., Keller, Mark P., Attie, Alan D., Saghatelian, Alan, Bisello, Alessandro, Gellman, Samuel H.
Source:
Journal of the American Chemical Society 2014 v.136 no.37 pp. 12848-12851
ISSN:
1520-5126
Subject:
G-protein coupled receptors, agonists, glucagon-like peptide 1, islets of Langerhans, noninsulin-dependent diabetes mellitus, peptidases, peptide hormones
Abstract:
Glucagon-like peptide-1 (GLP-1) is a natural agonist for GLP-1R, a G protein-coupled receptor (GPCR) on the surface of pancreatic β cells. GLP-1R agoinsts are attractive for treatment of type 2 diabetes, but GLP-1 itself is rapidly degraded by peptidases in vivo. We describe a design strategy for retaining GLP-1-like activity while engendering prolonged activity in vivo, based on strategic replacement of native α residues with conformationally constrained β-amino acid residues. This backbone-modification approach may be useful for developing stabilized analogues of other peptide hormones.
Agid:
5399447