title: A potent α/β-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 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.
authors.affiliation: Department of Chemistry, University of Wisconsin , Madison, Wisconsin 53706, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johnson
authors.forename: Stacey
authors.initials: S
authors.lastname: Barrick
authors.forename: Marlies V
authors.initials: MV
authors.lastname: Hager
authors.forename: Amanda
authors.initials: A
authors.lastname: McFedries
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Homan
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D055550:Protein Stability; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1