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

Eunice N. Murage, Guangzu Gao, Alessandro Bisello, Jung Mo Ahn

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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 α-helices in the N- and C-terminal regions simultaneously. In addition to improving the receptor activation capability (up to 5-fold) by fixing the α-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.

Original languageEnglish (US)
Pages (from-to)6412-6420
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number17
DOIs
StatePublished - Sep 9 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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