SYNTHESIS OF INSULIN MEDIATOR AND RELATED STRUCTURES

胰岛素介质及相关结构的合成

• 批准号: 3240237
• 负责人: TSUNG-YING SHEN
• 金额: $ 17.72万
• 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 1991-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240237
• 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 来自质膜的可溶性介质， 胰岛素样活性在几个生化测定。 结果 酶处理和成分分析表明， 结构可能类似于独特类型的糖基 磷脂酰肌醇复合物，其通常参与 锚定许多膜蛋白。 证实这一 结构假说，特别是定义立体化学 根据假设的部分结构，我们建议合成几种 用于比较的寡糖和糖脂衍生物 问题研究 这些包括2-氨基-2-脱氧-D-吡喃葡萄糖基-（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，作为简化模型， 糖基肌醇复合物。 在目前对a 胰岛素介质中的肽组分，相应的 还将合成肽衍生物。 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介质。 他们 还将在4项酶测定和1项完整细胞测定中进行评估 作为胰岛素介质的完全或部分激动剂或拮抗剂。 在中介体的正确部分结构被 一旦确定，它们将与载体蛋白偶联， 产生单克隆抗体。 这些抗体将 用于促进胰岛素介体的机制研究 以及糖基锚定的膜蛋白的图谱 磷脂酰肌醇 结构信息还将提供 为设计和合成光敏剂提供了合理的依据 作为生化物质的胰岛素介体的不可逆抑制剂 作为新型抗糖尿病药物的探针和口服活性胰岛素模拟物 剂.