Matrix Metalloproteinase Inhibition and Specificity

基质金属蛋白酶抑制和特异性

• 批准号: 7924939
• 负责人: Steven R Van Doren
• 金额: $ 20.45万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924939
• 关键词: 26S proteasome; Abdominal Aortic Aneurysm; Active Sites; Adverse effects; Affinity; Arthritis; Behavior; Binding; Biological Availability; Blood Vessels; Bronchitis; C-terminal; Cardiovascular Diseases; Cardiovascular system; Catalytic Domain; Cell Proliferation; Cessation of life; Characteristics; Charge; Chemopreventive Agent; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical Trials; Collaborations; Complement; Complex; Complication; Development; Disease; Disease Progression; Drug Delivery Systems; Elastases; Elastin; Engineering; Entropy; Epigallocatechin Gallate; Event; Fibronectins; Functional disorder; Gelatinase A; Gelatinase B; Glossary; Green tea; Growth Factor; Homeostasis; Human; Hydrogen; Hydrolysis; Industry; Inhibition of Matrix Metalloproteinases Pathway; Interstitial Collagenase; Knowledge; Lead; Link; Lung; Lung diseases; Malignant Neoplasms; Maps; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Muscle Rigidity; Mutagenesis; N-terminal; Neoplasm Metastasis; Pathway interactions; Peptides; Pharmaceutical Preparations; Plague; Play; Proteins; Pulmonary Emphysema; Recording of previous events; Relaxation; Research Personnel; Rheumatoid Arthritis; Role; Rupture; Serine Protease; Side; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Source; Specificity; Stimulation of Cell Proliferation; Stromelysin 1; Structure; Surface; Surveys; Testing; Therapeutic; Therapeutic Uses; Thermodynamics; Time; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Tissues; Trypsin; Variant; Vertebral column; Veterinary Medicine; Wound Healing; beta barrel; cooking; cost; design; drinking; drug development; elastase inhibitor; flexibility; gallocatechol; improved; inhibitor/antagonist; insight; macrophage; matrix metalloproteinase 12; methyl group; mouse model; neglect; novel; polyphenol; preference; professor; programs; protein protein interaction; receptor; reproductive; success; tumor growth

DESCRIPTION (provided by applicant): Matrix metalloproteinases (MMPs), and TIMPs that inhibit them, control tissue remodeling in cancer, arthritis, arterial disease, pulmonary disease, reproductive events, and wound healing. Mechanisms of action of two key natural MMP inhibitors are not adequately understood, i.e., the human protein TIMP-1 and the cancer preventative EGCG from green tea. The mechanisms of action of these two with therapeutic potential will be investigated further. The previous project found the high affinity of a typical TIMP and MMP to be driven by entropy gain, largely configurational. The backbone of the beta-barrel of N-TIMP-1 is mobilized upon binding of MMP-3. For a more complete spatial and temporal view of flexibility changes linked to their binding, NMR studies of mobility will be expanded to free and N-TIMP-1-bound states of MMP-3, to side chain methyl groups, and to longer time scales where thermodynamic inferences become more robust. Engineering of N-TIMP-1 to enhance therapeutic potential has neglected its undesirable growth factor activity. The previous project found a conserved surface on TIMPs hypothesized to mediate this activity. This patch will be mutagenized in an effort to remove N-TIMP-1's activity of stimulating cell proliferation. Signaling pathways and receptor mediating TIMP-1's growth factor activity will be identified. Inhibition of a few MMPs was found among the chemopreventative bioactivities of the main polyphenol in green tea, EGCG. Which MMPs are inhibited by EGCG will be surveyed. The novel mechanism of MMP inhibition by EGCG and its structural mode of binding an MMP will be investigated. A contemporary drug target for cardiovascular and pulmonary conditions is MMP-12. MMP-12 has distinctively high activity upon the elastin component of blood vessels and lungs and upon the elastin-preserving inhibitor of elastase known as a1-anti-trypsin. Sequence determinants of MMP-12's activity upon elastin and a1-anti-trypsin are not known and will be probed. Sites in MMP-12 that interact with a1-anti-trypsin will be mapped by NMR. Elastase specificity will be engineered out of MMP-12, and then transferred into MMP-3. Discovery of features that confer the unique specificity to MMP-12 should aid design of more selective inhibitors and may suggest determinants of specificities of other MMPs.

描述（由申请人提供）：基质金属蛋白酶（MMPs）和抑制它们的TIMPs，控制癌症、关节炎、动脉疾病、肺部疾病、生殖事件和伤口愈合中的组织重塑。两种关键的天然MMP抑制剂的作用机制尚未充分了解，即人类蛋白TIMP-1和绿茶中的抗癌EGCG。这两种具有治疗潜力的药物的作用机制有待进一步研究。先前的项目发现典型的TIMP和MMP的高亲和力是由熵增益驱动的，主要是构型的。N-TIMP-1的β -管骨架在与MMP-3结合时被动员。为了更完整地了解与它们结合有关的灵活性变化的空间和时间视图，迁移率的NMR研究将扩展到MMP-3的自由和n - timp -1结合状态，侧链甲基，以及更长的时间尺度，其中热力学推断变得更加可靠。N-TIMP-1的工程，以提高治疗潜力忽略了其不良的生长因子活性。先前的项目在timp上发现了一个保守的表面，假设它可以调节这种活动。该贴片将被诱变以去除N-TIMP-1刺激细胞增殖的活性。将确定介导TIMP-1生长因子活性的信号通路和受体。绿茶中主要多酚EGCG的化学预防生物活性中发现了对少数MMPs的抑制作用。我们将研究哪些MMPs被EGCG抑制。研究EGCG抑制MMP的新机制及其与MMP结合的结构模式。当前治疗心血管和肺部疾病的药物靶点是MMP-12。MMP-12对血管和肺部的弹性蛋白成分以及对弹性酶的弹性蛋白保存抑制剂a1-抗胰蛋白酶具有明显的高活性。MMP-12对弹性蛋白和a1-抗胰蛋白酶活性的序列决定因素尚不清楚，将进行探索。MMP-12中与a1-抗胰蛋白酶相互作用的位点将通过NMR绘制。弹性酶特异性将从MMP-12中提取，然后转移到MMP-3中。发现赋予MMP-12独特特异性的特征有助于设计更具选择性的抑制剂，并可能提示其他MMPs特异性的决定因素。