INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
批准号:
3222936
负责人:
HAROLD E VAN WART
金额:
$27.83万
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
项目状态:
已结题
起止时间:
1989-07-01 至 1994-06-30
中文摘要
破坏细胞外基质,包括胶原
构成牙周骨架的纤维
结缔组织,是炎症的主要后果
人类的牙周病。大量证据表明
这种细胞外基质的降解是由一种
高度同源的蛋白水解酶家族,由
内源性和炎性细胞。这些水解酶都是
被认为是锌金属酶,它们共同
称为基质金属蛋白酶(MMPs)。五大基质金属氧化物
包括成纤维细胞型胶原酶、明胶酶和基质分解酶,
中性粒细胞型胶原酶和明胶酶。虽然它是
目前认为这些基质金属蛋白酶的集体行动是
对牙周结缔组织的破坏负责
疾病,个体基质金属蛋白酶在实际中的确切作用
细胞介导的过程还不是很清楚。这样的知识
只有通过研究基质的降解才能得到
大分子由活细胞在其中整个分解代谢
机器完好无损。特定的基质金属蛋白酶的参与必须,
因此,要通过对它们的特异性抑制来评估。在这
研究五种基质金属蛋白酶的特定有效抑制剂
它们的制备及其阻断基质分解的效果
大分子(I、IV和V型胶原蛋白和明胶,
纤维连接蛋白、层粘连蛋白、蛋白多糖核心蛋白)
将对成纤维细胞和中性粒细胞进行评估。这些实验
应该能让我们确定每种基质金属蛋白酶在细胞中的作用-
介导对每种生理底物的破坏。设计
抑制剂的选择将基于对多肽的广泛研究
5种基质金属蛋白酶的底物特异性。抑制剂将
BE底物类似物,其中可剪断的多肽键被取代
带有官能团(亚磷酸酯、硫化物、亚硫醚、砜、
酮和氟酮)能够与活性物质相互作用
每种基质金属丝的锌原子位置。这一原则已被用于
之前开发血管紧张素转换酶抑制剂
它现在被广泛用于控制人类的高血压。
我们的数据表明,尽管同源性很高,但五种基质金属蛋白酶
具有完全不同的多肽底物特异性
允许构建高度特异的有效抑制剂
五种酶中的每一种。
英文摘要
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.
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EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
-
批准号:2183625
-
项目类别:
-
资助金额:$15.3万
-
财政年份:1991
-
负责人:HAROLD E VAN WART
-
依托单位:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
-
批准号:3305521
-
项目类别:
-
资助金额:$20.88万
-
财政年份:1991
-
负责人:HAROLD E VAN WART
-
依托单位:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
-
批准号:3305522
-
项目类别:
-
资助金额:$14.71万
-
财政年份:1991
-
负责人:HAROLD E VAN WART
-
依托单位:
EXTRACELLULAR REGULATION OF MATRIX METALLOPROTEINASES
-
批准号:3305523
-
项目类别:
-
资助金额:$14.15万
-
财政年份:1991
-
负责人:HAROLD E VAN WART
-
依托单位:
INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
-
批准号:3222938
-
项目类别:
-
资助金额:$29.52万
-
财政年份:1989
-
负责人:HAROLD E VAN WART
-
依托单位:
INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES
-
批准号:3222937
-
项目类别:
-
资助金额:$28.97万
-
财政年份:1989
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND COLLAGEN METABOLISM
-
批准号:3071253
-
项目类别:
-
资助金额:$5.25万
-
财政年份:1982
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND COLLAGEN METABOLISM
-
批准号:3071126
-
项目类别:
-
资助金额:$5.13万
-
财政年份:1982
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:2174913
-
项目类别:
-
资助金额:$13.3万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND CONNECTIVE TISSUE METABOLISM
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批准号:3275188
-
项目类别:
-
资助金额:$11.8万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND CONNECTIVE TISSUE METABOLISM
-
批准号:3275191
-
项目类别:
-
资助金额:$12.92万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND CONNECTIVE TISSUE METABOLISM
-
批准号:2175048
-
项目类别:
-
资助金额:$12.55万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274688
-
项目类别:
-
资助金额:$5.25万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274686
-
项目类别:
-
资助金额:$8.8万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND CONNECTIVE TISSUE METABOLISM
-
批准号:3275186
-
项目类别:
-
资助金额:$7.47万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274679
-
项目类别:
-
资助金额:$7.84万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274683
-
项目类别:
-
资助金额:$7.65万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274687
-
项目类别:
-
资助金额:$12.8万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYME DYNAMICS AND MECHANISM
-
批准号:3274682
-
项目类别:
-
资助金额:$16.88万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
METALLOENZYMES AND CONNECTIVE TISSUE METABOLISM
-
批准号:3275189
-
项目类别:
-
资助金额:$11.95万
-
财政年份:1980
-
负责人:HAROLD E VAN WART
-
依托单位:
海外基金