Huntington's Disease Natural Product Drug Discovery

描述(申请人提供)：亨廷顿病(HD)是一种神经疾病，由编码亨廷顿蛋白的IT15基因的CAG三联体重复基因突变引起。大量的现场数据表明，HTT的蛋白水解性片段(S)参与了HD的发病过程，导致严重的运动障碍。该项目的目标将是发现新的海洋天然产物化合物，作为亨廷顿病(HD)的潜在治疗剂。该项目填补了HD和神经退行性疾病领域的一项重大空白，为未来HD治疗药物的开发发现了新的蛋白酶抑制剂。此外，该项目使用新的海洋天然产物作为在蛋白酶靶区发现药物的独特机会，以减少参与HD的神经毒性HTT蛋白分解片段的产生。这个独特的项目将整合Viyan Hook博士在蛋白质生物化学和神经生物学方面的专业知识、William Gerwick博士发现治疗药物的海洋天然产品、纹状体神经细胞模型以及表达亨廷顿病突变Huntingtin(HTT)蛋白的转基因小鼠。来自加利福尼亚州圣地亚哥。该项目计划将在所需学科中实施三个经验丰富的实验室的跨学科努力，以发现亨廷顿蛋白蛋白分解的新型蛋白酶抑制剂，作为降低细胞突变HTT神经毒性的一种手段。该项目可以快速推进，因为合作实验室拥有所需的专业知识，并且位于加州大学圣地亚哥分校，彼此距离很近。该项目的HD药物发现将在两个具体目标下完成。第一个目的是评估海洋天然产物化合物对被认为与HD有关的蛋白酶活性的抑制作用，包括半胱氨酸天冬氨酸酶、钙蛋白酶、溶酶体蛋白(组织蛋白酶L、B和D)和基质金属蛋白酶10。蓝藻海洋天然产物化合物是一种丰富的有效药物分子来源，具有独特的结构多样性。在目标2中，蓝藻海洋天然化合物将在细胞检测中减少N-末端HTT片段并防止细胞死亡，使用表达全长突变Huntingtin(HTT)蛋白的纹状体样神经元细胞，并在表达正常HTT蛋白的对照细胞中进行测试。从目标1和目标2确定的有效化合物将根据它们的抑制能力优先考虑。这些化合物将被计划用于未来的R01项目，该项目将在HD小鼠模型中对化合物进行体内测试，以改善HD转基因小鼠的运动障碍。这些结果可以为HD药物开发提供候选的海洋天然药物化合物。 公共卫生相关性：亨廷顿病(HD)是一种神经疾病，会导致运动障碍和痴呆症。拟议的新项目的目标将是发现亨廷顿病(HD)的新治疗剂。这个独特的项目将整合三位专家的联合专业知识，他们分别是维维安·胡克博士、威廉·格威克博士和阿尔伯特·拉斯帕达博士在大学的维维安·胡克博士、威廉·格威克博士和阿尔伯特·拉斯帕达博士在蛋白酶和细胞生物化学、海洋天然产物药物发现以及细胞和遗传小鼠HD模型方面的专业知识。这将促进HD治疗剂的开发。

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is a neurological disorder resulting from CAG triplet repeat genetic mutation of the IT15 gene that encodes the huntingtin protein. Extensive data in the field indicate that proteolytic fragment(s) of htt mediate the HD disease process, resulting in severe motor disturbances. The goal of this project will be to discover novel marine natural product compounds as potential therapeutic agents for Huntington's disease (HD). This project fulfills a major gap in the HD and neurodegenerative disease field for discovery of novel agents as protease inhibitors for future development of therapeutic agents for HD. Furthermore, this project uses novel marine natural products as a unique opportunity for drug discovery in the protease target area to reduce production of neurotoxic htt proteolytic fragments that participate in HD. This unique project will integrate expertise in protease biochemistry and neurobiology by Dr. Vivian Hook, marine natural products for discovery of therapeutic agents by Dr. William Gerwick, and model striatal neuronal cells, as well as transgenic mice, expressing mutant huntingtin (htt) protein of Huntington's disease by Dr. Albert La Spada at the Univ. of Calif., San Diego. The project plan will implement interdisciplinary efforts of three highly experienced laboratories in the required disciplines to discover novel protease inhibitors of huntingtin protein proteolysis as a means to reduce cellular mutant htt neurotoxicity. This project can progress at a rapid pace since the collaborating laboratories have the required expertise, and are located in close proximity to one another at UC San Diego. HD drug discovery of this project will be accomplished in two specific aims. The first aim will evaluate marine natural product compounds for inhibition of protease activities thought to be involved in HD, which includes caspase, calpain, lysosomal proteases (cathepsins L, B, and D), and matrix metalloprotease 10. Cyanobacteria algal marine natural product compounds are a rich source of potent drug molecules with unique structural diversity. In aim 2, cyanobacterial marine natural compounds will be tested in cellular assays for reduction of N-terminal htt fragments and protection from cell death, using striatal-like neuronal cells that express full-length mutant huntingtin (htt) protein, and in control cells expressing normal htt protein. Effective compounds identified from aims 1 and 2 will be prioritized by their inhibitory potencies. These compounds will be planned for a future R01 project that will conduct in vivo testing of compounds in HD mouse models for effectiveness to improve the motor impairment in HD transgenic mice. Results can indicate candidate marine natural drug compounds for HD drug development. PUBLIC HEALTH RELEVANCE: Huntington's Disease (HD) is a neurological disorder resulting in motor disturbances as well as dementia. The goal of the proposed new project will be to discover novel therapeutic agents for Huntington's disease (HD). This unique project will integrate the joint expertise of three experts in protease and cellular biochemistry, marine natural product drug discovery, and cellular with genetic mouse models of HD by Dr. Vivian Hook, Dr. William Gerwick, and Dr. Albert La Spada, respectively, at the Univ. of Calif., San Diego that will facilitate development of therapeutic agents for HD.