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来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，尽管如此，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，吸收太慢了。因此，我们寻求开发具有显著改善性能的第二代速效胰岛素类似物，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胰岛素全化学合成方法，以提供高效的折叠/形成二硫化物。简便的化学合成胰岛素将使广泛的非编码氨基酸的结合，以系统地调整胰岛素分子的性质。我们将准备一系列设计的胰岛素化学类似物，用于糖尿病动物模型的生物物理表征、受体结合试验和生物学测试。我们设计的第二代胰岛素类似物的目标包括：(1)更快的起效；（ii）较短的诉讼期限；（iii）增强物理稳定性；（iv）增强化学稳定性；(v)增强的受体选择性。我们的研究有望拓展胰岛素治疗的化学空间，首次开拓现代药物化学的宝库。

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.