INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
抑制细胞外基质金属蛋白酶
基本信息
- 批准号:3222938
- 负责人:
- 金额:$ 29.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1989
- 资助国家:美国
- 起止时间:1989-07-01 至 1994-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Destruction of the extracellular matrix, including the collagen
fibers which constitute the skeletal framework of periodontal
connective tissues, is a major consequence of inflammatory
periodontal disease in humans. A body of evidence suggests that
this degradation of the extracellular matrix is catalyzed by a
family of highly homologous proteinases that are released by
endogenous and inflammatory cells. These proteinases are all
believed to be zinc metalloenzymes and they are collectively
referred to as matrix metalloproteinases (MMP). The five major MMP
include fibroblast-type collagenase, gelatinase, and stromelysin,
and neutrophil-type collagenase and gelatinase. While it is
presently believed that the collective action of these MMP is
responsible for the destruction of connective tissue in periodontal
disease, the precise roles of the individual MMP in the actual
cell-mediated process is not yet well understood. Such knowledge
can only be obtained from the study of the degradation of matrix
macromolecules by live cells in which the entire catabolic
machinery is intact. The involvement of specific MMP must,
therefore, be assessed through their specific inhibition. In this
study specific potent inhibitors of each of the five MMP will be
prepared and their efficacy in blocking the breakdown of matrix
macromolecules (types I, IV and V collagens and gelatins,
fibronectin, laminin, proteoglycan core protein) by live
fibroblasts and neutrophils will be assessed. These experiments
should allow us to establish the role of each MMP in the cell-
mediated destruction of each physiological substrate. The design
of the inhibitors will be based on extensive studies of the peptide
substrate specificity of each of the five MMP. The inhibitors will
be substrate analogs in which the scissile peptide bond is replaced
with a functional group (phosphinate, sulfide, sulfoxide, sulfone,
ketone and fluoroketone) capable of interacting with the active
site zinc atom of each MMP. This principle has been used
previously to develop inhibitors of angiotensin converting enzyme
which are now being widely used to control hypertension in humans.
Our data indicate that, although highly homologous, the five MMP
have sufficiently different peptide substrate specificities to
permit construction of potent inhibitors which are highly specific
for each of the five enzymes.
破坏细胞外基质,包括胶原蛋白
纤维构成牙周的骨骼框架
结缔组织,是炎症的主要后果
牙周病的危害 大量证据表明,
细胞外基质的这种降解是由
高度同源的蛋白酶家族,由
内源性和炎性细胞。 这些蛋白酶都
被认为是锌金属酶,它们共同
称为基质金属蛋白酶(MMP)。 五大MMP
包括成纤维细胞型胶原酶、明胶酶和溶基质素,
和明胶酶。 虽然
目前认为,这些MMP的集体行动是
负责破坏牙周结缔组织
疾病,个别MMP在实际中的确切作用
细胞介导的过程尚未被很好地理解。 这种知识
只能从基质降解的研究中获得
大分子通过活细胞,其中整个分解代谢
机器完好无损。 特定MMP的参与必须,
因此,可以通过其特异性抑制作用进行评估。 在这
研究特异性的有效抑制剂的每一个五个MMP将是
制备和它们在阻断基质分解中的功效
大分子(I、IV和V型胶原蛋白和明胶,
纤连蛋白、层粘连蛋白、蛋白聚糖核心蛋白)
将评估成纤维细胞和中性粒细胞。 这些实验
应该可以让我们确定每个MMP在细胞中的作用-
介导的每种生理底物的破坏。 设计
的抑制剂将基于肽的广泛研究,
五种MMP中每一种的底物特异性。 抑制剂将
是底物类似物,其中易断裂的肽键被替换,
与官能团(次膦酸酯,硫化物,亚砜,砜,
酮和氟酮)能够与活性物质相互作用
每个MMP的位点锌原子。 这一原则已被用于
以前开发血管紧张素转换酶抑制剂
其现在被广泛用于控制人类的高血压。
我们的数据表明,虽然高度同源,五个MMP
具有足够不同的肽底物特异性,
允许构建高度特异性的有效抑制剂,
五种酶的每一种。
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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HAROLD E VAN WART其他文献
HAROLD E VAN WART的其他文献
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{{ truncateString('HAROLD E VAN WART', 18)}}的其他基金
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
基质金属蛋白酶的细胞外调节
- 批准号:
2183625 - 财政年份:1991
- 资助金额:
$ 29.52万 - 项目类别:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
基质金属蛋白酶的细胞外调节
- 批准号:
3305521 - 财政年份:1991
- 资助金额:
$ 29.52万 - 项目类别:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
基质金属蛋白酶的细胞外调节
- 批准号:
3305522 - 财政年份:1991
- 资助金额:
$ 29.52万 - 项目类别:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
基质金属蛋白酶的细胞外调节
- 批准号:
3305523 - 财政年份:1991
- 资助金额:
$ 29.52万 - 项目类别:
INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
抑制细胞外基质金属蛋白酶
- 批准号:
3222936 - 财政年份:1989
- 资助金额:
$ 29.52万 - 项目类别:
INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
抑制细胞外基质金属蛋白酶
- 批准号:
3222937 - 财政年份:1989
- 资助金额:
$ 29.52万 - 项目类别:
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