化学
受体
胰高血糖素
胰高血糖素样肽1受体
兴奋剂
肽
胰高血糖素受体
胰高血糖素样肽-1
生物化学
生物活性
内分泌学
内科学
糖尿病
2型糖尿病
激素
生物
体外
医学
作者
Andreas Evers,Torsten Haack,Martin Lorenz,Martin Bossart,Ralf Elvert,Bernd Henkel,Siegfried Stengelin,Michael Kurz,Maike Glien,Angela Dudda,Katrin Lorenz,Dieter Kadereit,Michael R. Wagner
标识
DOI:10.1021/acs.jmedchem.7b00174
摘要
Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.
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