Development of long-acting glucose-responsive insulin formulations

长效葡萄糖反应性胰岛素制剂的开发

• 批准号: 10055540
• 负责人: Danny Hung-Chieh Chou
• 金额: $ 64.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055540
• 关键词: Acids; Animal Model; Binding; Biochemical; Blood; Blood Glucose; Cellular Assay; Cessation of life; Charge; Chemicals; Clinic; Dangerousness; Development; Diabetes Mellitus; Effectiveness; Excipients; FDA approved; Family suidae; Formulation; Generations; Glucose; Glucose Clamp; Glucose tolerance test; Health; Hyperglycemia; Hypoglycemia; Immune response; In Vitro; Incidence; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Isoelectric Point; Lead; Location; Long-Acting Insulin; Measures; Modeling; Modification; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Property; Rattus; Repression; Risk; Rodent; Series; Serum; Solubility; Stream; Therapeutic; Work; absorption; aggressive therapy; analog; base; blood glucose regulation; clinical translation; compliance behavior; design; diabetes risk; diabetic; glargine; glycemic control; improved; in vivo; in vivo evaluation; innovation; next generation; novel; novel therapeutics; pandemic disease; prototype; response; subcutaneous; therapeutic lead compound

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.

尽管胰岛素类似物显著改善了糖尿病患者的血糖控制，但血糖升高的风险仍然存在。 波动仍然很高，包括低血糖导致的死亡和 葡萄糖水平的次优控制。本提案旨在通过制定一项 改善胰岛素类似物，葡萄糖响应性胰岛素（GRI）的产生，其将直接响应于 血糖水平。当血糖水平升高时，这些GRI将使胰岛素最大限度地发挥作用 但当血糖水平低时，它会抑制胰岛素。因此他们会允许积极的治疗 同时避免了低血糖的风险，并将为治疗提供巨大的进步。 糖尿病我们最近通过开发一种化学修饰的胰岛素证明了这种方法的潜力 通过掺入用于葡萄糖传感的苯基硼酸使其具有葡萄糖响应性。在这 我们将合成一系列新一代胰岛素衍生物，旨在提高胰岛素的生物利用度。 葡萄糖反应性和低葡萄糖条件下增强的阻遏，表征其有效性 在生物化学和细胞分析中，对设计进行了改进，并在动物中验证了它们的潜力 模型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。