IDENTIFICATION OF SMALL MOLECULE INHIBITORS FOR CASPASE-2 AND CASPASE-6

CASPASE-2 和 CASPASE-6 小分子抑制剂的鉴定

• 批准号: 8362277
• 负责人: YI TANG
• 金额: $ 0.03万
• 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/8362277
• 关键词: Attenuated; Biological Assay; Caspase; Cells; Cleaved cell; Crystallography; Cysteine Protease; Dementia; Disease; Drug Delivery Systems; Enzymes; Funding; Genes; Goals; Grant; Huntington Disease; Individual; Mutation; National Center for Research Resources; Neurodegenerative Disorders; Pathology; Personality; Principal Investigator; Proteins; Radiation; Research; Research Infrastructure; Resources; Source; United States National Institutes of Health; Work; base; caspase-2; caspase-6; cost; high throughput screening; human Huntingtin protein; inhibitor/antagonist; motor control; mutant; small molecule; structural biology; therapeutic target

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. Huntington?s Disease (HD) is a fatal neurodegenerative disease, which results from a mutation in the gene encoding the Huntingtin protein. The mutant protein is cleaved into toxic fragments by a class of cysteine proteases called caspases. Individuals afflicted with the disease develop loss of motor control, personality changes, and dementia. The goal of this work aims to inhibit the cleavage of the mutant Huntingtin protein by caspase-2 and caspase-6 in order to validate these two enzymes as therapeutic targets and to identify compounds that attenuate the accumulation of toxic Htt fragments involved in the pathology of the disease. Compounds identified through high-throughput screenings will be characterized and validated by x-ray crystallography prior to the application in cell-based assays. The long-term goals of the project are to validate caspase-2 and caspase-6 as drug targets and develop cures for Huntington?s Disease.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 亨廷顿？亨廷顿氏病（HD）是一种致命的神经退行性疾病，其起因于编码亨廷顿蛋白的基因突变。突变蛋白被称为半胱氨酸蛋白酶的一类半胱氨酸蛋白酶切割成有毒片段。患有这种疾病的人会失去运动控制，人格改变和痴呆。这项工作的目的是抑制突变亨廷顿蛋白的切割半胱天冬酶-2和半胱天冬酶-6，以验证这两种酶作为治疗靶点，并确定化合物，减弱参与疾病的病理毒性Htt片段的积累。通过高通量筛选鉴定的化合物将在应用于基于细胞的测定之前通过X射线晶体学进行表征和验证。该项目的长期目标是验证caspase-2和caspase-6作为药物靶点，并开发治疗亨廷顿？的疾病。