title: Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges.
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.
authors.affiliation: Department of Chemistry, University of Texas at Dallas, Richardson, Texas 75080,USA.
authors.forename: Eunice N
authors.initials: EN
authors.lastname: Murage
authors.forename: Guangzu
authors.initials: G
authors.lastname: Gao
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
mesh_terms: D002460:Cell Line; D002942:Circular Dichroism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015260:Neprilysin / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D018027:Receptors, Glucagon / Q000819:agonists*; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007769:Lactams; D010456:Peptides, Cyclic; D018027:Receptors, Glucagon; D012996:Solutions; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin