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

设计、全合成

• 批准号: 8113870
• 负责人: STEPHEN B.H. KENT
• 金额: $ 37.19万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113870
• 关键词: Affinity; Amino Acid Substitution; Amino Acids; Animal Model; Beta Cell; Binding; Biological; Biological Assay; Biological Testing; Biotechnology; Chemicals; Clinical; Collaborations; Crystallization; Crystallography; Custom; Data; Diabetes Mellitus; Disulfides; Drug Formulations; Drug Kinetics; Edetic Acid; Electrostatics; Esters; Family suidae; Functional RNA; Generations; Goals; Guanidines; Halogens; Human; Hypoglycemia; In Vitro; Indiana; Insulin; Insulin Infusion Systems; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor Receptor; Link; Long-Acting Insulin; Measures; Mediating; Methods; Modification; Monitor; NMR Spectroscopy; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Poison; Predisposition; Preparation; Proinsulin; Property; Proteins; Protocols documentation; Rattus; Relative (related person); Research; Route; Series; Streptozocin; Surrogate Markers; Testing; Therapeutic; Thermodynamics; Time; Universities; X-Ray Crystallography; Zinc; absorption; analog; aryl halide; base; chemical stability; chemical synthesis; design; diabetic; diabetic rat; frontier; glycemic control; improved; interest; male; novel; polypeptide; public health relevance; receptor; receptor binding; three dimensional structure

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. PUBLIC HEALTH RELEVANCE: "Our goal is to develop a second-generation rapid-acting insulin analog with substantially improved properties in order to provide additional benefits to patients. We will prepare a series of designed chemical analogs of insulin for biophysical characterization, receptor binding assays, and biological testing in animal models of diabetes mellitus. Our proposed research promises to expand the chemical space of insulin therapeutics to exploit for the first time the armamentarium of modern medicinal chemistry."

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。目前的快速作用类似物是15年前生物技术的开创性胜利，但由于吸收太晚，无法实现理想的进餐血糖控制，也无法安全有效地使用自动胰岛素泵。因此，我们寻求开发一种具有显著改进特性的第二代快速作用胰岛素类似物，以便为患者提供额外的好处。为此，我们首先提出了一种新的胰岛素全化学合成的优化和应用，该合成提供了高效的二硫化物的折叠/形成。胰岛素的简便化学合成将使一系列非编码氨基酸的结合成为可能，以便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、受体结合分析和生物学测试。我们第二代胰岛素类似物的设计目标包括：(I)更快的起效；(Ii)更短的作用时间；(Iii)增强的物理稳定性；(Iv)增强的化学稳定性；以及(V)增强的受体选择性。我们提出的研究承诺扩大胰岛素治疗的化学空间，首次开发现代药物化学的兵器。 与公众健康相关：我们的目标是开发性能大幅改善的第二代快速作用胰岛素类似物，以便为患者提供额外的好处。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、受体结合分析和生物学测试。我们拟议的研究承诺扩大胰岛素疗法的化学空间，首次开发现代药物化学的宝库。