Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin

描述（由申请人提供）：I型糖尿病（DM）的最佳控制通常需要速效和长效胰岛素类似物的组合，以实现严格的血糖控制。目前的速效类似物是15年前生物技术的先驱性胜利，但是对于理想的餐时血糖控制或安全有效地使用自动胰岛素泵来说，吸收太延迟。因此，我们寻求开发第二代速效胰岛素类似物，其具有显著改善的性质，以便为患者提供额外的益处。为此，我们首先提出优化和应用一种新的全化学合成胰岛素，提供高效的折叠/形成二硫化物。胰岛素的简易化学合成将使得能够掺入广泛的非编码氨基酸，以便系统地调节胰岛素分子的性质。我们将制备一系列设计的胰岛素化学类似物，用于DM动物模型的生物物理表征、受体结合试验和生物学试验。我们对第二代胰岛素类似物的设计目标包括：（i）起效更快;（ii）作用持续时间更短;（iii）物理稳定性增强;（iv）化学稳定性增强;（v）受体选择性增强。我们提出的研究有望扩大胰岛素治疗的化学空间，首次利用现代药物化学的设备。

DESCRIPTION (provided by applicant): Optimal control of Type I diabetes mellitus (DM) often requires a combination of rapid- acting and long-acting insulin analogs to achieve tight glycemic control. Current rapid- acting analogs, a pioneering triumph of biotechnology 15 years ago, are nonetheless too delayed in absorption for either ideal meal-time glycemic control or the safe and effective use of automated insulin pumps. We therefore seek to develop a second-generation rapid-acting insulin analog with substantially improved properties in order to provide additional benefits to patients. To this end, we first propose to optimize and apply a novel total chemical synthesis of insulin that provides for highly efficient folding/formation of disulfides. Facile chemical synthesis of insulin will enable the incorporation of a wide range of non-coded amino acids in order to systematically tune the properties of the insulin molecule. We will prepare a series of designed chemical analogs of insulin for biophysical characterization, receptor binding assays, and biological testing in animal models of DM. Our design goals for a second-generation insulin analog include: (i) faster onset of action; (ii) briefer duration of action; (iii) enhanced physical stability; (iv) enhanced chemical stability; and (v) enhanced receptor selectivity. Our proposed research promises to expand the chemical space of insulin therapeutics to exploit for the first time the armamentarium of modern medicinal chemistry.