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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Murage EN,Gao G,Bisello A,Ahn JM

doi

10.1021/jm100602m

subject

Has Abstract

pub_date

2010-09-09 00:00:00

pages

6412-20

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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