INHIBITION OF EXTRACELLULAR MATRIX METALLOPROTEINASES

抑制细胞外基质金属蛋白酶

• 批准号: 3222937
• 负责人: HAROLD E VAN WART
• 金额: $ 28.97万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/3222937
• 关键词: collagenase; endopeptidases; enzyme inhibitors; extracellular matrix; fibroblasts; fibronectins; gelatin; ketones; laminin; metalloenzyme; neutrophil; phosphines; proteoglycan; sulfides; sulfones; sulfoxide; zinc

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.

细胞外基质的破坏，包括胶原蛋白 构成牙周骨骼框架的纤维 结缔组织是炎症的主要结果 人类的牙周病。 大量证据表明 细胞外基质的这种降解是由A催化的 由高度同源蛋白酶的家族释放 内源性和炎症细胞。 这些蛋白酶都是 相信是锌金属酶，它们是统称的 称为基质金属蛋白酶（MMP）。 五个主要的MMP 包括成纤维细胞型胶原酶，明胶酶和Stromelysin， 和中性粒细胞型胶原酶和明胶酶。 虽然是 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，单个MMP在实际的实际作用 细胞介导的过程尚不清楚。 这样的知识 只能从矩阵降解的研究中获得 活细胞的大分子，其中整个分解代谢 机械完好无损。 特定MMP的参与必须 因此，可以通过其特定抑制进行评估。 在这个 研究五个MMP中每一个的特定有效抑制剂将是 准备及其在阻止矩阵故障的功效 大分子（I型，IV和V胶原蛋白和明胶， 纤连蛋白，层粘连蛋白，蛋白聚糖核心蛋白）活 将评估成纤维细胞和中性粒细胞。 这些实验 应该使我们能够确定每个MMP在细胞中的作用 介导的每种生理底物的破坏。 设计 抑制剂将基于对肽的广泛研究 五个MMP中每个的底物特异性。 抑制剂会 是替换剪刀肽键的底物类似物 与功能组（磷酸，硫化物，硫化物，硫酮， 酮和氟酮）能够与活性相互作用 每个MMP的位点锌原子。 该原则已被使用 以前要开发血管紧张素转化酶的抑制剂 现在广泛用于控制人类的高血压。 我们的数据表明，尽管高度同源，但五个MMP 具有足够不同的肽底物特异性 允许建造高度特异性的有效抑制剂 对于五种酶中的每一个。