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A potent ?/?-peptide analogue of GLP-1 with prolonged action in vivo.

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 ? 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 ? residues with conformationally constrained ?-amino acid residues. This backbone-modification approach may be useful for developing stabilized analogues of other peptide hormones.

SUBMITTER: Johnson LM

PROVIDER: S-EPMC4183665 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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A potent α/β-peptide analogue of GLP-1 with prolonged action in vivo.

Johnson Lisa M LM Barrick Stacey S Hager Marlies V MV McFedries Amanda A Homan Edwin A EA Rabaglia Mary E ME Keller Mark P MP Attie Alan D AD Saghatelian Alan A Bisello Alessandro A Gellman Samuel H SH

Journal of the American Chemical Society 20140905 37

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-mod ...[more]

PMID: 25191938

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