Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. A primary challenge has been the naturally short half-life of GLP-1 due to its rapid proteolytic degradation in vivo. Whereas mutagenesis and lipidation strategies have yielded clinical agents, we developed an alternative approach to preserving the structure and function of GLP-1 by all-hydrocarbon i, i + 7 stitching. This particular “stitch” is especially well-suited for reinforcing and protecting the structural fidelity of GLP-1. Lead constructs demonstrate striking proteolytic stability and potent biological activity in vivo. Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.

中文翻译：

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胰高血糖素样肽-1受体的碳氢化合物缝合的肽激动剂。

胰高血糖素样肽1（GLP-1）是在胰腺β细胞上发现的GLP-1受体（GLP-1R）的天然肽激动剂。受体的参与以葡萄糖依赖性方式刺激胰岛素释放并增加β细胞质量，这是2型糖尿病药物治疗的两个理想特征。因此，已经集中精力开发用于治疗应用的基于GLP-1的GLP-1R肽激动剂。主要挑战是由于GLP-1在体内的快速蛋白水解降解作用，其自然半衰期短。尽管诱变和脂质化策略已产生临床作用，但我们开发了另一种方法，可以通过全烃i，i保留GLP-1的结构和功能。+ 7针。这种特殊的“针迹”特别适合增强和保护GLP-1的结构保真度。领先的建筑业表现出惊人的蛋白水解稳定性和体内强大的生物活性。因此，我们报告了一种简便的方法来生成用于血糖控制的替代GLP-1R激动剂。