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

设计、全合成

基本信息

批准号：
8473857
负责人：
STEPHEN B.H. KENT
金额：
$ 35.53万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473857
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

项目摘要

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.

描述（由申请人提供）：对I型糖尿病（DM）的最佳控制通常需要快速作用和长效胰岛素类似物的结合，以实现紧密的血糖控制。目前的快速作用类似物是15年前生物技术的开创性胜利，尽管如此，对于理想的餐食血糖控制或安全有效地使用自动化胰岛素泵，但仍太延迟了吸收。因此，我们试图开发第二代快速作用胰岛素类似物，具有大大改善的特性，以便为患者提供额外的好处。为此，我们首先建议优化和应用新型的胰岛素总化学合成，从而提供高效的二硫化物折叠/形成。胰岛素的便捷化学合成将使融合多种非编码氨基酸，以系统地调整胰岛素分子的特性。我们将在DM动物模型中准备一系列设计的胰岛素化学类似物，以进行生物物理表征，受体结合测定和生物学测试。我们的第二代胰岛素类似物的设计目标包括：（i）动作速度更快；（ii）英国的行动时间；（iii）增强的身体稳定性；（iv）增强的化学稳定性；（v）增强的受体选择性。我们提出的研究有望扩大胰岛素治疗剂的化学空间，以首次利用现代药物化学的武术。