Medicinal Chemistry and Biology of Oral Insulin Mimics

口服胰岛素模拟物的药物化学和生物学

• 批准号: 6897476
• 负责人: MICHAEL C PIRRUNG
• 金额: $ 22.24万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897476
• 关键词: binding proteins; biomimetics; chemical registry /resource; combinatorial chemistry; drug design /synthesis /production; growth factor receptors; high throughput technology; hydrolysis; indoles; insulin; intermolecular interaction; oral administration; protein tyrosine kinase

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop orally active insulin mimetic drugs based on novel paradigms for the development of small molecule ligands for growth factor receptors. This goal will be accomplished by synthesis of natural product libraries using combinatorial chemistry and their screening against receptor tyrosine kinases, It will be aided by the identification of cytoplasmic proteins that bind to the novel insulin mimetic natural product demethylasterriquinone B1 (DAQ B1), and by direct examination of the interactions of DAQ B 1 with the insulin receptor cytoplasmic domain. The ultimate outcome of this research would be elimination of the need for insulin injections. This project will utilize the following methods: organic synthesis, medicinal and combinatorial chemistry, phage display cloning, and protein chemistry. Assays of the products will include in vitro and in cyto insulin receptor activation, and study of their cytotoxic and cellular transport properties. This research will be significant because substances that can elicit the same biological response as insulin but that are not proteins, and therefore may be orally active, would be of significant value in diabetes management. They would eliminate the need for hypodermic syringes/needles, obviating concerns about contamination and increasing the convenience of administration, with a likely enhancement in patient compliance. They would therefore increase the reliability of diabetes management, particularly for children.

描述（由申请人提供）：这项研究的长期目标是基于新型范式开发口服胰岛素模拟药物，以开发用于生长因子受体的小分子配体。该目标将通过使用组合化学及其针对受体酪氨酸激酶的筛查来实现，这将通过鉴定与新型胰岛素模拟天然产物Demethylysriquinone B1（DAQ B1）以及通过结合的细胞质蛋白来帮助。直接检查DAQ B 1与胰岛素受体细胞质结构域的相互作用。这项研究的最终结果是消除对胰岛素注射的需求。该项目将利用以下方法：有机合成，药用和组合化学，噬菌体显示克隆和蛋白质化学。产品的测定将包括体外和环胰岛素受体激活，以及研究其细胞毒性和细胞转运特性。这项研究将是重要的，因为可以引起与胰岛素相同的生物学反应但不是蛋白质的物质，因此可能是口服活性的，在糖尿病管理中具有重要价值。他们将消除对皮下注射注射器/针的需求，从而消除了对污染的担忧和增加给药的便利性，并有可能提高患者依从性。因此，它们将提高糖尿病管理的可靠性，特别是对于儿童。