Department of Neurobiology and Center for Drug Discovery, Duke University Medical Center, 4321 Medical Park Drive, Durham, NC 27704, USA.
Neurotherapeutics. 2013 Jul;10(3):400-15. doi: 10.1007/s13311-013-0195-4.
Huntington's disease (HD) typifies a class of inherited neurodegenerative disorders in which a CAG expansion in a single gene leads to an extended polyglutamine tract and misfolding of the expressed protein, driving cumulative neural dysfunction and degeneration. HD is invariably fatal with symptoms that include progressive neuropsychiatric and cognitive impairments, and eventual motor disability. No curative therapies yet exist for HD and related polyglutamine diseases; therefore, substantial efforts have been made in the drug discovery field to identify potential drug and drug target candidates for disease-modifying treatment. In this context, we review here a range of early-stage screening approaches based in in vitro, cellular, and invertebrate models to identify pharmacological and genetic modifiers of polyglutamine aggregation and induced neurodegeneration. In addition, emerging technologies, including high-content analysis, three-dimensional culture models, and induced pluripotent stem cells are increasingly being incorporated into drug discovery screening pipelines for protein misfolding disorders. Together, these diverse screening strategies are generating novel and exciting new probes for understanding the disease process and for furthering development of therapeutic candidates for eventual testing in the clinical setting.
亨廷顿病 (HD) 是一类遗传性神经退行性疾病的典型代表，在这类疾病中，单个基因中的 CAG 扩展导致延伸的多聚谷氨酰胺链和表达蛋白的错误折叠，从而导致累积的神经功能障碍和退化。HD 是一种不可避免的致命疾病，其症状包括进行性神经精神和认知障碍，最终导致运动障碍。目前尚无针对 HD 和相关多聚谷氨酰胺疾病的治愈疗法；因此，药物发现领域已经做出了大量努力，以确定潜在的药物和药物靶点候选物，用于疾病修饰治疗。在这方面，我们在这里回顾了一系列基于体外、细胞和无脊椎动物模型的早期筛选方法，以鉴定多聚谷氨酰胺聚集和诱导的神经退行性变的药理学和遗传学修饰物。此外，新兴技术，包括高内涵分析、三维培养模型和诱导多能干细胞，越来越多地被纳入蛋白质错误折叠疾病的药物发现筛选管道。总之，这些不同的筛选策略为理解疾病过程提供了新颖而令人兴奋的新探针，并为最终在临床环境中进行治疗候选药物的开发提供了进一步的支持。
