Development of long-acting glucose-responsive insulin formulations

尽管胰岛素类似物显著改善了糖尿病患者的血糖控制，但患糖尿病的风险 短途旅行仍然居高不下，包括死于低血糖和因 血糖水平的次优控制。这项建议旨在通过开发一种 改善胰岛素类似物，葡萄糖反应性胰岛素(GRI)的生成，它将直接对 血糖水平。当血糖水平升高时，这些GRI将允许胰岛素最大限度地活跃 但在血糖水平较低时会使胰岛素失活。因此，他们会允许激进的治疗 在避免低血糖风险的同时减少高血糖，并将在治疗方面取得显著进展 糖尿病的症状。我们最近通过开发一种化学修饰的胰岛素来展示这种方法的潜力。 这是通过掺入苯基硼酸进行葡萄糖传感而使其对葡萄糖敏感的。在这 提议，我们将合成一系列下一代胰岛素衍生物，这些衍生物是为增加 低糖条件下的葡萄糖响应性和增强的抑制，表征了它们的有效性 在生化和细胞分析中，反复改进设计，并在动物身上验证其潜力 模特。成功的结果将导致治疗前的先导化合物提供胰岛素活性的控制 并有可能从根本上改善糖尿病的治疗。

Although insulin analogs have markedly improved glycemic control in people with diabetes, the risk of glycemic excursions remains high, including death from hypoglycemia and a multitude of major negative impacts from suboptimal control of glucose levels. This proposal seeks to overcome these problems by developing an improved generation of insulin analogs, glucose-responsive insulins (GRIs), which would directly respond to blood sugar levels. These GRIs would allow insulin to be maximally active when blood sugar levels are elevated but would inactivate insulin when blood sugar levels are low. They would therefore allow the aggressive treatment of hyperglycemia while avoiding the risk of hypoglycemia, and would provide a dramatic advance in the treatment of diabetes. We recently demonstrated the potential of this approach by developing a chemically modified insulin that was made glucose-responsive by the incorporation of a phenylboronic acid for glucose sensing. In this proposal, we will synthesize a series of next-generation insulin derivatives that are designed for increased glucose responsiveness and enhanced repression under low glucose conditions, characterize their effectiveness in biochemical and cellular assays, iterate improvements to the design, and validate their potential in an animal model. Successful outcome will result in pre-therapeutic lead compounds that provide control of insulin activity and has the potential to radically improve the treatment of diabetes.