袁钧英：大规模药物筛选发现能减缓退行性病变的药物分子
生物谷报道：大规模药物筛选在国际上已成为药物筛选的主要手段之一。由知名的华人科学家袁钧英等在上海张江成立的新药筛选公司--国家新药筛选中心最近结出新成果，发现一组可以延缓退行性病变的药物分子。这一研究成果发表在最近出版的PNAS杂志上。
细胞的溶酶体自噬现象是机体清除许多异物，或非正常折叠的蛋白质，以及细胞代谢中留下的一些细胞器和长生存蛋白（long-lived proteins）的主要方式。但是，在神经元中，如果自噬现象减弱的庆，就会出现许多未折叠蛋白在细胞内累及，导致慢性神经退行性疾病的产生，如亨廷顿氏病，老年性痴呆等。因此，如果能发现有药物促进或改善细胞的自噬功能，则有望用于治疗这类疾病。国家新药筛选中心科学家通过基于图像直接观察的方法进行大规模小分子药物的筛选，发现有8种小分子药物具有促进细胞自噬功能，其中7种成分是FDA批准可以用于疾病药物的。这一研究目前在培养的细胞中得到了多次重复。生物谷专家认为，这一研究强烈提示，改善细胞的自噬功能，有望成为新型的药物开发的靶点。结合中国中草药单体数据库的巨大优势，有望从其中筛选出一两种具有临床应用价值的新型一类药物，为人类作出真正的贡献。国家新药筛选中心这一靶点的选择具有前瞻性，这也体现了新药筛选中心的科学家团队的智慧。
Autophagy is a lysosome-dependent cellular catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. Reduction of autophagy activity has been shown to lead to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. To explore the mechanism of autophagy and identify small molecules that can activate it, we developed a series of high-throughput image-based screens for small-molecule regulators of autophagy. This series of screens allowed us to distinguish compounds that can truly induce autophagic degradation from those that induce the accumulation of autophagosomes as a result of causing cellular damage or blocking downstream lysosomal functions. Our analyses led to the identification of eight compounds that can induce autophagy and promote long-lived protein degradation. Interestingly, seven of eight compounds are FDA-approved drugs for treatment of human diseases. Furthermore, we show that these compounds can reduce the levels of expanded polyglutamine repeats in cultured cells. Our studies suggest the possibility that some of these drugs may be useful for the treatment of Huntington's and other human diseases associated with the accumulation of misfolded proteins.
原始出处：
Lihong Zhang, Jia Yu, Heling Pan, Ping Hu, Yan Hao, Wenqing Cai, Hong Zhu, Albert D. Yu, Xin Xie, Dawei Ma, and Junying Yuan
PNAS published November 16, 2007, 10.1073/pnas.0709695104 ( Cell Biology )
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