DEVELOPMENT OF ISOFORM-SELECTIVE INHIBITORS OF NITRIC OXIDE SYNTHASES (NOS)

一氧化氮合酶 (NOS) 异构体选择性抑制剂的开发

• 批准号: 8362210
• 负责人: HUIYING LI
• 金额: $ 0.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362210
• 关键词: Animal Testing; Biological Assay; Brain Hypoxia; Cerebral Palsy; Complex; Development; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Funding; Generations; Grant; In Vitro; Modification; National Center for Research Resources; Nitric Oxide Synthase; Principal Investigator; Protein Isoforms; Radiation; Research; Research Infrastructure; Resources; Source; Structure; United States National Institutes of Health; base; cost; design; information gathering; inhibitor/antagonist; pre-clinical; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Development of isoform selective NOS inhibitors continues to be the central focus of this proposal. Based on structural information gathered during the two previous proposal periods, a new generation of nNOS selective inhibitors were designed de novo (ref. 1). The new compounds were screened through in vitro inhibitory assays. Those shown to have good potency and selectivity were then used for structural studies. The best inhibitors were also found to protect against cerebral palsy induced by brain hypoxia in pre-clinical animal tests (ref.2). The enzyme-inhibitor complex structures are critical for further modification and improvement of new inhibitors.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 异构体选择性 NOS 抑制剂的开发仍然是该提案的核心焦点。根据前两个提案期间收集的结构信息，从头设计了新一代 nNOS 选择性抑制剂（参考文献 1）。通过体外抑制试验筛选新化合物。然后将那些显示出良好效力和选择性的物质用于结构研究。在临床前动物试验中还发现最好的抑制剂可以预防因脑缺氧引起的脑瘫（参考文献2）。 酶-抑制剂复合物结构对于新抑制剂的进一步修饰和改进至关重要。