Novel PAI-1 Inhibitors of Neutrophil Proteinases

新型 PAI-1 中性粒细胞蛋白酶抑制剂

• 批准号: 6443540
• 负责人: Duane Ellington Day
• 金额: $ 9.96万
• 依托单位: MOLECULAR INNOVATIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6443540
• 关键词: arginine; cathepsin G; chemical kinetics; elastases; gene mutation; neutrophil; peptide chemical synthesis; phenylalanine; plasminogen activator inhibitors; protease inhibitor; protein engineering; site directed mutagenesis; valine

DESCRIPTION (provided by applicant): This proposal aims to examine the feasibility of using plasminogen activator inhibitor type 1 (PaI-i) mutants as inhibitors of the neutrophil proteinases, neutrophil elastase and cathepsin G. Native PAI-i is not an inhibitor of neutrophil enzymes but preliminary studies presented in this grant show that its specificity can be readily changed by site directed mutagenesis. Apart from inhibiting neutrophil proteinases, other properties of PAI-i make it an attractive candidate for a therapeutic for pathologies involving tissue destruction by neutrophil proteinases. Unlike the endogenous inhibitors of neutrophil proteinases, PAI-i is an effective inhibitor of surface bound proteinases. In addition, PAI-i in complex with proteinases is cleared by receptor-mediated endocytosis more efficiently than the endogenous inhibitors. Our colleagues at the Holland Laboratories of the American Red Cross demonstrate that a single amino acid mutation in reactive center bond of PAI-i converts it to an effective inhibitor of pancreatic elastase without affecting receptor-mediated endocytosis. Based on these findings we propose to design and produce specific PAI-i mutants that inhibit the neutrophil elastase and cathepsin G. PROPOSED COMMERCIAL APPLICATIONS: Pulmonary diseases, such as those caused by cigarette smoke and genetic deficiency are associated with serious tissue damage caused by the proteinases neutrophil elastase and cathepsin G. A current therapy for hereditary emphysema (deficiency of alpha one proteinase inhibitor) is replacement with fractions of human plasma containing the missing inhibitor. The current treatment is of limited availability. There are more than 100,000 hereditary emphysema sufferers in the US alone. Development PAI-1 mutants targeted to neutrophil elastase and cathepsin G provide a strong commercialization potential for a superior alternative to current therapies treating emphysema and offer the hope of treating other inflammatory diseases.

描述（由申请人提供）：本提案旨在审查