MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS
新型抗血栓药物的药物化学
基本信息
- 批准号:3347148
- 负责人:
- 金额:$ 18.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROBERT R RANDO其他文献
ROBERT R RANDO的其他文献
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{{ truncateString('ROBERT R RANDO', 18)}}的其他基金
Retinyl Ester Binding Proteins and the Visual Cycle
视黄酯结合蛋白和视觉周期
- 批准号:
7001202 - 财政年份:2005
- 资助金额:
$ 18.06万 - 项目类别:
Retinyl Ester Binding Proteins and the Visual Cycle
视黄酯结合蛋白和视觉周期
- 批准号:
6855567 - 财政年份:2005
- 资助金额:
$ 18.06万 - 项目类别:
Retinyl Ester Binding Proteins and the Visual Cycle
视黄酯结合蛋白和视觉周期
- 批准号:
7176097 - 财政年份:2005
- 资助金额:
$ 18.06万 - 项目类别:
AMINOGLYCOSIDE/RNA INTERACTIONS AND CORNEAL INFECTIONS
氨基糖苷/RNA 相互作用和角膜感染
- 批准号:
6476401 - 财政年份:1998
- 资助金额:
$ 18.06万 - 项目类别:
AMINOGLYCOSIDE/RNA INTERACTIONS AND CORNEAL INFECTIONS
氨基糖苷/RNA 相互作用和角膜感染
- 批准号:
6625011 - 财政年份:1998
- 资助金额:
$ 18.06万 - 项目类别:
AMINOGLYCOSIDE/RNA INTERACTIONS AND CORNEAL INFECTIONS
氨基糖苷/RNA 相互作用和角膜感染
- 批准号:
6329574 - 财政年份:1998
- 资助金额:
$ 18.06万 - 项目类别:
AMINOGLYCOSIDE/RNA INTERACTIONS AND CORNEAL INFECTIONS
氨基糖苷/RNA 相互作用和角膜感染
- 批准号:
6125153 - 财政年份:1998
- 资助金额:
$ 18.06万 - 项目类别:
AMINOGLYCOSIDE/RNA INTERACTIONS AND CORNEAL INFECTIONS
氨基糖苷/RNA 相互作用和角膜感染
- 批准号:
2739207 - 财政年份:1998
- 资助金额:
$ 18.06万 - 项目类别:
MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS
新型抗血栓药物的药物化学
- 批准号:
3347146 - 财政年份:1985
- 资助金额:
$ 18.06万 - 项目类别:
MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS
新型抗血栓药物的药物化学
- 批准号:
3347153 - 财政年份:1985
- 资助金额:
$ 18.06万 - 项目类别:
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