SYNTHESIS OF INSULIN MEDIATOR AND RELATED STRUCTURES

胰岛素介质及相关结构的合成

• 批准号: 3240238
• 负责人: TSUNG-YING SHEN
• 金额: $ 17.14万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-06-01 至 1992-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240238
• 关键词: cell membrane; chemical structure function; chemical synthesis; glycolipids; hormone regulation /control mechanism; insulin inhibitor; insulin sensitivity /resistance; insulinlike factor; laboratory mouse; laboratory rabbit; laboratory rat; membrane proteins; membrane structure; oligosaccharides; phosphatidylinositols; phospholipids; sugar phosphates; transport proteins

Recent studies have shown that insulin stimulates the release of a soluble mediator(s) from the plasma membrane which produces insulin-like activities in several biochemical assays. Results from enymatic treatment and composition analysis indicated that its structure may be analogous to a unique type of glycosyl phosphatidylinositol complex, which is commonly involved in the anchoring of many membrane proteins. To substantiate this structural hypothesis and especially to define the stereochemistry of postulated partial structures, we propose to synthesize several oligosaccharide and glycolipid derivatives for comparative studies. These inlcude 2-amino-2-deoxy-D-glucopyroanosyl-(alpha or beta) - (1, 4 or 1, 3 or 1, 5)-myo-inositol-1-phosphate (1), 6-0- (2-aminoethoxyphosphoryl)-D-mannose (2), phospholipid derivatives of 1, and conjugates of 1 and 2 as simplified models of the glycosyl inositol complex. Pending the current analysis of a peptide component in the insulin mediator, the corresponding peptide derivatives will also be synthesized. These compounds will be compared with degradation products of the insulin mediator in spectroscopic and chromatographic systems. They will also be evaluated in 4 enzyme assays and one intact cell assay as full or partial agonists or antagonists of the insulin mediator. After the correct partial structures of the mediator are identified, they will be coupled to carrier proteins for the generation of monoclonal antibodies. These antibodies will be used to facilitate the mechanistic studies of the insulin mediator and the mapping of membrane proteins anchored by glycosyl phosphatidylinositol. The structural information will also provide a rational basis for the design and synthesis of photoactive irreversible inhibitors of the insulin mediator as biochemical probes and orally active insulin-mimics as novel anti-diabetic agents.

最近的研究表明，胰岛素刺激释放一种 从质膜中产生的可溶性介质(S) 几种生化分析中的胰岛素样活性。结果来自 酶处理和成分分析表明，其 结构可能类似于一种独特类型的糖基 磷脂酰肌醇复合体，它通常参与 许多膜蛋白的锚定。来证实这一点 结构假说，特别是对立体化学的定义 对于假设的部分结构，我们建议合成几个 用于比较的低聚糖和糖脂衍生物 学习。这些化合物包括2-氨基-2-脱氧-D-葡萄糖基-(α- 或β)-(1，4或1，3或1，5)-肌醇-1-磷酸(1)，6-0- (2-氨基乙氧基磷酰基)-D-甘露糖(2)，磷脂 1的导数，以及1和2的共轭作为简化的模型 糖基肌醇复合体。等待当前对 胰岛素介体中的多肽成分，相应的 还将合成多肽衍生物。这些化合物 将与胰岛素的降解产物进行比较 光谱和色谱系统中的中间体。他们 也将在4种酶检测和1种完整细胞检测中进行评估 作为胰岛素介体的全部或部分激动剂或拮抗剂。 在介体的正确部分结构被 鉴定后，它们将与载体蛋白偶联，用于 单抗的产生。这些抗体将是 用于促进胰岛素介体的机理研究 糖基锚定的膜蛋白图谱 磷脂酰肌醇。结构信息还将提供 光活性物质设计与合成的合理依据 作为生化作用的胰岛素介体不可逆抑制物 新型抗糖尿病药物--探针剂和口服活性胰岛素模拟物 探员们。