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.

中文翻译：

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基于新型Exendin的双胰高血糖素样肽1（GLP-1）/胰高血糖素受体激动剂的设计。

胰高血糖素样肽1（GLP-1）和胰高血糖素受体的双重激活有可能导致新的治疗糖尿病的治疗原理。在这里，我们报告了一系列通过合理设计发现的对这些受体具有双重活性的新型肽。在序列分析和基于结构的设计的基础上，将胰高血糖素的结构元件工程化为选择性GLP-1受体激动剂exendin-4，从而产生具有强大的双重GLP-1 /胰高血糖素受体活性的杂合肽。显示了详细的结构-活动关系数据。用非天然氨基酸和修饰氨基酸进行的进一步修饰产生了新的代谢稳定肽，这些肽在糖尿病db / db小鼠的慢性研究中显示出显着的剂量依赖性血糖降低，并且在饮食诱导的肥胖（DIO）小鼠中降低了体重。通过NMR光谱的结构分析证实，这些肽以其特征性的色氨酸-笼状折叠基序保持了exendin-4-like结构，这是有利的化学和物理稳定性的原因。