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， 生理激活需要它成为膜结合。发生这种情况 通过同时存在钙、酸性磷脂如 磷脂酰丝氨酸（PS）和甘油二酯。后者的存在是 具有重要的监管意义，因为它是 多磷脂酰肌醇周转甘油二酯的需求可以是 对佛波醇等结构多样的肿瘤促进剂感到满意 酯类、杀鱼素和脱溴阿氏藻毒素。PKC可能是 肿瘤促进剂的重要靶点。此外，PKC还发挥着 在血小板聚集、心脏功能和神经系统中的重要作用 功能这项补助金的主要重点是了解 PKC的新激活过程。特别感兴趣的是 揭示了PKC激活剂功能的结构基础。一方面 另一方面，PKC对化学结构具有极强的选择性， 甘油二酯激活剂。同时，结构多样的肿瘤 属于二萜、肽和大环内酯系列的启动子可以 都能有效地激活酶这些意见在这里得到调和 随着PKC新的统一结构假说的提出， 这些活化剂是根据进度报告中所述的实验确定的。 这一新的假设对新型甘油二酯和 肽类似物应与激酶有效地相互作用。这些 分子将被合成和研究作为推定的PKC激活剂， 抑制剂的最后，将制备新的环状PS类似物以研究 PKC磷脂结合位点的特异性。 本文还对活化剂结合位点的性质进行了补充研究。 预期。PKC调节结构域结合位点将被共价结合。 用基于活化剂的光亲和探针标记，并且标记区域 将被排序。 综合起来，这些研究应该使我们更接近于理解 PKC在分子水平上的调节以及如何调节的一般问题 蛋白质可以与膜相互作用并结合到膜上。最后，结构 这里获得的信息将用于绘制PKC甘油二酯 结合位点，并可用作制备强效 酶的抑制剂。