1. Development of Potent Glucagon-like Peptide-1 Agonists with High Enzyme Stability via Introduction of Multiple Lactam Bridges
- Author
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Jung-Mo Ahn, Guangzu Gao, Alessandro Bisello, and Eunice N. Murage
- Subjects
Lactams ,Stereochemistry ,Dipeptidyl Peptidase 4 ,Peptides, Cyclic ,Glucagon-Like Peptide-1 Receptor ,Protein Structure, Secondary ,Cell Line ,Structure-Activity Relationship ,chemistry.chemical_compound ,Glucagon-Like Peptide 1 ,Drug Discovery ,Receptors, Glucagon ,Humans ,Hypoglycemic Agents ,Neprilysin ,chemistry.chemical_classification ,Circular Dichroism ,Receptor interaction ,Glucagon-like Peptide-1 Agonists ,Combinatorial chemistry ,Solutions ,Enzyme ,chemistry ,Lactam ,Molecular Medicine ,Receptor activation - 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 of96 h). These highly constrained peptides are the first examples of NEP 24.11-resistant GLP-1 analogues.
- Published
- 2010