Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges

J Med Chem. 2010 Sep 9;53(17):6412-20. doi: 10.1021/jm100602m.

Abstract

Glucagon-like peptide-1 (GLP-1) has the ability to lower the blood glucose level, and its regulatory functions make it an attractive therapeutic agent for the treatment of type 2 diabetes. However, its rapid degradation by enzymes like dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) 24.11 severely compromises its effective clinical use. Whereas specific DPP-IV inhibitors have been developed, NEP 24.11 targets multiple sites in the GLP-1 sequence, which makes it difficult to block. To address this drawback, we have designed and synthesized conformationally constrained GLP-1 analogues by introducing multiple lactam bridges that stabilized both alpha-helices in the N- and C-terminal regions simultaneously. In addition to improving the receptor activation capability (up to 5-fold) by fixing the alpha-helical conformations required for optimal receptor interaction, the introduced lactam bridges provided outstanding shielding over NEP 24.11 (half-life of >96 h). These highly constrained peptides are the first examples of NEP 24.11-resistant GLP-1 analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Circular Dichroism
  • Dipeptidyl Peptidase 4 / chemistry*
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / chemical synthesis
  • Glucagon-Like Peptide 1 / chemistry
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology
  • Neprilysin / chemistry*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Protein Structure, Secondary
  • Receptors, Glucagon / agonists*
  • Solutions
  • Structure-Activity Relationship

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Lactams
  • Peptides, Cyclic
  • Receptors, Glucagon
  • Solutions
  • Glucagon-Like Peptide 1
  • Dipeptidyl Peptidase 4
  • Neprilysin