Glucagon-like peptide-1 (GLP-1) is of particular interest for treating type 2 diabetes mellitus (T2DM), as it induces insulin secretion in a glucose-dependent fashion and has the potential to facilitate weight control. However, native GLP-1 is a short incretin peptide that is susceptible to fast proteolytic inactivation and rapid clearance from the circulation. Various GLP-1 analogs and bioconjugation of GLP-1 analogs have been developed to counter these issues, but these modifications are frequently accompanied by the sacrifice of potency and the induction of immunogenicity. Here, we demonstrated that with the conjugation of a zwitterionic polymer, poly(carboxybetaine) (pCB), the pharmacokinetic properties of native GLP-1 were greatly enhanced without serious negative effects on its potency and secondary structure. The pCB conjugated GLP-1 further provided glycemic control for up to 6 days in a mouse study. These results illustrate that the conjugation of pCB could realize the potential of using native GLP-1 for prolonged glycemic control in treating T2DM.

中文翻译：

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两性离子聚合物与胰高血糖素样肽1结合，可长期控制血糖。

胰高血糖素样肽1（GLP-1）对于治疗2型糖尿病（T2DM）尤为重要，因为它以葡萄糖依赖性方式诱导胰岛素分泌，并具有促进体重控制的潜力。但是，天然GLP-1是短的肠降血糖素肽，易于快速蛋白水解失活和从循环中快速清除。已经开发出各种GLP-1类似物和GLP-1类似物的生物缀合来解决这些问题，但是这些修饰经常伴随着效力的牺牲和免疫原性的诱导。在这里，我们证明了通过两性离子聚合物，聚（羧基甜菜碱）（pCB）的缀合，天然GLP-1的药代动力学特性得到了极大的增强，而对它的效能和二级结构没有严重的负面影响。在小鼠研究中，缀合了pCB的GLP-1还提供了长达6天的血糖控制。这些结果说明，pCB的缀合可以实现使用天然GLP-1进行T2DM治疗中长期血糖控制的潜力。