Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's Aβ peptide and reduce its cytotoxicity.
Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's Aβ peptide and reduce its cytotoxicity.
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DOI：
10.1021/ja107552s
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发表时间：
2010-12-01
影响因子：
15
通讯作者：
Hecht MH
中科院分区：
文献类型：
--
作者：
Chen J;Armstrong AH;Koehler AN;Hecht MH
淀粉样蛋白-β（Aβ）聚集途径是努力发现预防或延迟阿尔茨海默病发作的疗法的关键靶标。然而，合理药物设计的努力受到有毒聚合物确切性质的不确定性的阻碍。相比之下，化合物文库的高通量筛选不需要详细了解毒性物质的结构，并且可以为发现可能导致有效治疗的小分子提供无偏见的方法。在这里，我们表明，小分子微阵列（SMM）代表了一个特别有前途的工具，用于识别化合物，结合Aβ肽。筛选表面固定有数千种化合物的微阵列载玻片与荧光标记的Aβ的结合。通过SMM筛选，鉴定了79个化合物，并测定了它们对Aβ诱导的PC 12细胞杀伤的抑制作用。进一步的实验集中于探索这些化合物之一的拯救机制：电子显微镜和刚果红结合显示该化合物增强原纤维形成，并表明它可能通过加速Aβ聚集通过早期毒性寡聚体来拯救细胞。这些发现表明，SMM筛选与Aβ的结合可有效识别降低Aβ毒性的化合物，并可揭示潜在的治疗线索，而不会出现专注于聚集抑制剂的方法中固有的偏倚。
The amyloid-β (Aβ) aggregation pathway is a key target in efforts to discover therapeutics that prevent or delay the onset of Alzheimer’s disease. Efforts at rational drug design, however, are hampered by uncertainties about the precise nature of the toxic aggregate. In contrast, high-throughput screening of compound libraries does not require a detailed understanding of the structure of the toxic species, and can provide an unbiased method for the discovery of small molecules that may lead to effective therapeutics. Here, we show that small molecule microarrays (SMMs) represent a particularly promising tool for identifying compounds that bind the Aβ peptide. Microarray slides with thousands of compounds immobilized on their surface were screened for binding to fluorescently labeled Aβ. 79 compounds were identified by the SMM screen, and then assayed for their ability to inhibit the Aβ-induced killing of PC12 cells. Further experiments focused on exploring the mechanism of rescue for one of these compounds: Electron microscopy and Congo red binding showed that the compound enhances fibril formation, and suggest that it may rescue cells by accelerating Aβ aggregation past an early toxic oligomer. These findings demonstrate that the SMM screen for binding to Aβ is effective at identifying compounds that reduce Aβ toxicity, and can reveal potential therapeutic leads without the biases inherent in methods that focus on inhibitors of aggregation.
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影响因子：
11.2
作者：
Klunk, WE;Engler, H;Långström, B
通讯作者：
Långström, B
DOI：
10.1073/pnas.1237107100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Hoshi, M;Sato, M;Sato, K
通讯作者：
Sato, K
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
影响因子：
4
作者：
Kim, Woojin;Kim, Yunkyoung;Hecht, Michael H.
通讯作者：
Hecht, Michael H.
影响因子：
16.6
作者：
Barnes-Seeman, D;Park, SB;Schreiber, SL
通讯作者：
Schreiber, SL