Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists

J Med Chem. 2015 May 14;58(9):4080-5. doi: 10.1021/acs.jmedchem.5b00166. Epub 2015 Apr 16.


Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Circular Dichroism
  • Cricetulus
  • Cyclic AMP / biosynthesis
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology
  • Protein Structure, Secondary
  • Radioligand Assay
  • Receptors, Glucagon / agonists*
  • Structure-Activity Relationship


  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Peptides, Cyclic
  • Receptors, Glucagon
  • Cyclic AMP