Zhang Minhua, Luo Guangrui, Zhou Yanjiao, Wang Shaohui, Zhong Zhong
1GlaxoSmithKline (China) R&D Company Limited, Neurodegeneration DPU, Shanghai, China.
J Biomol Screen. 2014 Jan;19(1):1-16. doi: 10.1177/1087057113499777. Epub 2013 Aug 19.
Neurodegenerative diseases affect millions of people worldwide, and the incidences increase as the population ages. Disease-modifying therapy that prevents or slows disease progression is still lacking, making neurodegenerative diseases an area of high unmet medical need. Target-based drug discovery for disease-modifying agents has been ongoing for many years, without much success due to incomplete understanding of the molecular mechanisms underlying neurodegeneration. Phenotypic screening, starting with a disease-relevant phenotype to screen for compounds that change the outcome of biological pathways rather than activities at certain specific targets, offers an alternative approach to find small molecules or targets that modulate the key characteristics of neurodegeneration. Phenotypic screens that focus on amelioration of disease-specific toxins, protection of neurons from degeneration, or promotion of neuroregeneration could be potential fertile grounds for discovering therapeutic agents for neurodegenerative diseases. In this review, we will summarize the progress of compound screening using these phenotypic-based strategies for this area, with a highlight on unique considerations for disease models, assays, and screening methodologies. We will further provide our perspectives on how best to use phenotypic screening to develop drug leads for neurodegenerative diseases.
神经退行性疾病影响着全球数百万人，且随着人口老龄化发病率不断上升。目前仍缺乏能够预防或减缓疾病进展的疾病修饰疗法，这使得神经退行性疾病成为一个医疗需求远未满足的领域。针对疾病修饰药物的基于靶点的药物研发已经进行了多年，但由于对神经退行性变潜在分子机制的理解不完整，并未取得太多成功。表型筛选从与疾病相关的表型出发，筛选能够改变生物途径结果而非特定靶点活性的化合物，为寻找调节神经退行性变关键特征的小分子或靶点提供了一种替代方法。专注于改善疾病特异性毒素、保护神经元免于退化或促进神经再生的表型筛选，可能是发现神经退行性疾病治疗药物的潜在沃土。在本综述中，我们将总结使用这些基于表型的策略在该领域进行化合物筛选的进展，重点关注疾病模型、检测方法和筛选方法的独特考量。我们还将进一步阐述如何最好地利用表型筛选来开发神经退行性疾病的药物先导物。
