Huntington's Disease Natural Product Drug Discovery

描述（由申请人提供）：亨廷顿病（HD）是一种神经系统疾病，由编码亨廷顿蛋白的IT 15基因的CAG三联重复基因突变引起。本领域的大量数据表明，htt的蛋白水解片段介导HD疾病过程，导致严重的运动障碍。本项目的目标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个主要空白，即发现新型药物作为蛋白酶抑制剂，用于HD治疗药物的未来开发。此外，该项目使用新型海洋天然产物作为蛋白酶靶向区域药物发现的独特机会，以减少参与HD的神经毒性htt蛋白水解片段的产生。这个独特的项目将整合Vivian Hook博士在蛋白酶生物化学和神经生物学方面的专业知识，William Gerwick博士用于发现治疗剂的海洋天然产物，以及加利福尼亚大学Albert La Spada博士的模型纹状体神经元细胞和转基因小鼠，表达亨廷顿病的突变亨廷顿（htt）蛋白，圣地亚哥该项目计划将实施三个经验丰富的实验室在所需学科的跨学科的努力，以发现新的蛋白酶抑制剂亨廷顿蛋白的蛋白水解作为一种手段，以减少细胞突变htt神经毒性。该项目可以快速进展，因为合作实验室具有所需的专业知识，并且在UC San Diego彼此靠近。该项目的HD药物发现将在两个具体目标中完成。第一个目的是评价海洋天然产物化合物对被认为参与HD的蛋白酶活性的抑制作用，所述蛋白酶包括半胱天冬酶、钙蛋白酶、溶酶体蛋白酶（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具有独特的结构多样性，是强效药物分子的丰富来源。在目标2中，蓝藻海洋天然化合物将在细胞测定中进行测试，以减少N-末端htt片段并保护细胞免于死亡，使用表达全长突变亨廷顿蛋白（htt）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2中鉴定的有效化合物将根据其抑制效力进行优先排序。这些化合物将计划用于未来的R 01项目，该项目将在HD小鼠模型中进行化合物的体内测试，以有效改善HD转基因小鼠的运动障碍。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：亨廷顿氏病（HD）是一种神经系统疾病，可导致运动障碍和痴呆。该项目的目标是发现治疗亨廷顿病（HD）的新药物。这个独特的项目将整合蛋白酶和细胞生物化学、海洋天然产物药物发现以及HD遗传小鼠模型的三位专家的联合专业知识，分别由加利福尼亚大学的Vivian Hook博士、William Gerwick博士和Albert La Spada博士完成，圣地亚哥，这将促进HD治疗药物的开发。

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.