期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 17, 页码 6412-6420出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm100602m
关键词
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资金
- American Diabetes Association [7-07-JF-02]
- Juvenile Diabetes Research Foundation [37-2009-103]
- Robert A. Welch Foundation [AT-1595]
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 24.1-resistant GLP-1 analogues.
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