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

J Am Chem Soc. 2014 Sep 17;136(37):12848-51. doi: 10.1021/ja507168t. Epub 2014 Sep 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / drug therapy
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / chemistry
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Stability
  • Receptors, Glucagon / agonists*


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1