IGFBP 3 LIGAND INHIBITORS FOR THE TREATMENT OF DIABETES

用于治疗糖尿病的 IGFBP 3 配体抑制剂

• 批准号: 2017767
• 负责人: NICHOLAS C LING
• 金额: $ 10万
• 依托单位: NEUROCRINE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-15 至 1997-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2017767
• 关键词: 3T3 cells; NOD mouse; binding proteins; blood glucose; diabetes mellitus; diabetes mellitus therapy; drug screening /evaluation; hypoglycemic agents; inhibitor /antagonist; insulinlike growth factor; ligands; nonhuman therapy evaluation; streptozotocin

DESCRIPTION (Adapted from applicant's abstract): Insulin-like growth factor-I (IGFI) is an important anabolic peptide which mimics many of the actions of insulin and growth hormone. IGFI has insulin-like metabolic and trophic effects and promotes the expression of many differentiated functions. The majority of IGFI circulates in blood as a biologically inactive trimolecular complex of 150 kDa consisting of IGF-binding protein-3 (IGFBP-3), an acid labile subunit (ALS) and IGFI. Ligands or drugs which inhibit the interaction of IGFI with IGFBP-3 should increase biologically active levels of free IGFI in plasma and have utility for the treatment of insulin and non-insulin dependent diabetes. Here the investigators propose to (1) Determine the effects of a selective peptide IGFBP-3 ligand inhibitor, [L24, 59, 60, A31] hIGFI, which does not interact with IGF or insulin receptors, on blood glucose levels in animal models of diabetes and (2) Validate a high throughput screening assay for human IGFBP-3 and screen an in-house chemical library of about 45,000 organic molecules in order to identify a non-peptide lead. The second phase of the proposal will optimize the non-peptide small molecule leads using a directed chemistry approach for the development of orally active drugs for the treatment of insulin and non-insulin dependent diabetes.

描述(摘自申请者摘要)：胰岛素样生长 胰岛素样生长因子-I(IGFI)是一种重要的合成代谢多肽，它与许多 胰岛素和生长激素的作用。IGFI有胰岛素样物质 代谢和营养作用并促进许多 差异化的功能。大多数IGFI在血液中循环为 一种150 kDa的生物活性三分子络合物，由 胰岛素样生长因子结合蛋白-3(IGFBP-3)、酸性不稳定亚单位(ALS)和IGFI。 抑制IGFI与IGFBP-3相互作用的配体或药物 应增加血浆和组织中游离IGFI的生物活性水平 对胰岛素和非胰岛素依赖型糖尿病的治疗有实用价值 糖尿病。在这里，调查人员建议(1)确定影响 选择性多肽IGFBP-3配体抑制剂[L24，59，60，A31] 血液中不与IGF或胰岛素受体相互作用的hIGFI 糖尿病动物模型的血糖水平和(2)验证了高血糖 人胰岛素样生长因子结合蛋白-3的通过量筛选和室内筛选 约45,000个有机分子的化学库，以识别 非肽类的铅。该提案的第二阶段将优化 使用定向化学方法的非肽小分子先导 用于治疗胰岛素的口服活性药物的开发 和非胰岛素依赖型糖尿病。