MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

新型抗血栓药物的药物化学

• 批准号: 3347148
• 负责人: ROBERT R RANDO
• 金额: $ 18.06万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3347148
• 关键词: anticoagulants; calcium; chemical structure function; diterpenes; drug design /synthesis /production; enzyme induction /repression; heart function; hormone regulation /control mechanism; macrolide antibiotics; neurotransmitters; phosphatidylinositols; phosphatidylserines; platelet aggregation; protein kinase C; stereochemistry

Protein kinase C (PKC) is an important regulatory enzyme whose physiological activation requires it to become membrane-bound. This occurs via the simultaneous presence of calcium, an acidic phospholipid such as phosphatidyl serine (PS), and a diglyceride. The presence of the latter is of great regulatory significance because it is the product of polyphosphatidylinositol turnover. The diglyceride requirement can be satisfied by structurally diverse tumor promoters such as the phorbol esters, teleocidin, and the debromoaplysiatoxins. It is likely that PKC is an important target for the tumor promoters. In addition, PKC plays an important role in platelet aggregation, cardiac function, and neural function. The major focus of this grant is to understand the mechanism of the novel activation process of PKC. Of particular interest is the unravelling the structural basis for PKC activator function. On the one hand, PKC is exceedingly selective with respect to the chemical structure of diglyceride activators. At the same time, structurally diverse tumor promoters belonging to the diterpene, peptide, and macrolide series , can all potently activate the enzyme. These observations are reconciled here with the presentation of a new unifying structural hypothesis on PKC activators which are based on experiments described in the progress report. This new hypothesis makes predictions concerning novel diglyceride and peptide analogs which should potently interact with the kinase. These molecules will be synthesized and studied as putative PKC activators and inhibitors. Finally, novel cyclic PS analogs will be prepared to study the specificity of the phospholipid binding-site of PKC. Complimentary studies on the nature of activator binding-site are also anticipated. The PKC regulatory domain binding-site will be covalently labeled with activator-based photoaffinity probes and the labeled region will be sequenced. Taken together, these studies should bring us closer to an understanding of the regulation of PKC at a molecular level and the general issue of how proteins can interact with and bind to membranes. Finally, the structural information obtained here will serve to map the PKC diglyceride binding-site and can be used as a starting point to prepare potent inhibitors of the enzyme.

蛋白激酶C（PKC）是一种重要的调节酶 生理激活要求它成为膜结合。发生这种情况 通过同时存在钙，酸性磷脂 磷脂酰丝氨酸（PS）和二甘油二酸酯。后者的存在是 具有很大的监管意义，因为它是 多磷脂酰肌醇更新。二甘油二酸酯的需求可能是 由结构上多样化的肿瘤启动子（例如佛波尔）满足 酯，远程神经素和脱布透析毒素。 PKC可能是 肿瘤启动子的重要目标。此外，PKC扮演 在血小板聚集，心脏功能和神经中的重要作用 功能。这笔赠款的主要重点是了解 PKC的新型激活过程。特别感兴趣的是 阐明PKC激活函数的结构基础。在一个 手，PKC相对于化学结构具有极大的选择性 二甘油类激活剂。同时，结构上多样的肿瘤 属于二萜，肽和大环内酯类系列的启动子可以 全部都有效激活酶。这些观察结果在这里调和 提出了PKC上新的统一结构假设 基于进度报告中描述的实验的激活剂。 这个新的假设有关于新型二甘油类药物和 肽类似物应与激酶有效相互作用。这些 分子将被合成并研究为推定的PKC激活剂和 抑制剂。最后，新颖的环状PS类似物将准备好研究 PKC的磷脂结合位点的特异性。 关于激活剂结合位置性质的免费研究也是 预期。 PKC调节域的结合位置将共价 用基于激活剂的光性探针和标记的区域标记 将被测序。 综上所述，这些研究应该使我们更加了解 PKC在分子水平上的调节，以及如何的一般问题 蛋白质可以与膜相互作用并结合。最后，结构 此处获得的信息将用于映射PKC二甘油类药物 绑定位置，可用作准备有效的起点 酶的抑制剂。