Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.
Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.
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DOI：
10.1111/cbdd.12341
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发表时间：
2014-11
影响因子：
3
通讯作者：
Hecht MH
中科院分区：
文献类型：
--
作者：
McKoy AF;Chen J;Schupbach T;Hecht MH
抑制淀粉样β（Aβ）肽的聚集可能是对抗阿尔茨海默病的有效策略。由于毒性Aβ聚集体的高分辨率结构未知，因此不可能合理设计小分子抑制剂，最好通过高通量筛选分离抑制剂。我们对65 000个化合物进行了高通量筛选，以确定化合物D737是Aβ聚集的抑制剂。D737减少了寡聚体和纤维的形成，并降低了Aβ42诱导的细胞毒性。最重要的是，D737增加了阿尔茨海默病的黑腹果蝇模型中转基因果蝇的寿命和运动能力（J Biol Chem，287，2012，38992）。为了探索使D737成为Aβ42聚集和毒性的有效抑制剂的化学特征，我们测试了D737的11个类似物的小集合。总体而言，化合物抑制Aβ聚集的能力是其延长中枢神经系统中表达人Aβ42的转基因果蝇寿命和运动能力的有效性的良好预测因子。两个芳香环上带有氟取代基的化合物（D744和D830）是Aβ42聚集的有效抑制剂，并且增加了转基因果蝇的寿命，超过了母体化合物D737所观察到的。
Inhibiting aggregation of the amyloid‐beta (Aβ) peptide may be an effective strategy for combating Alzheimer's disease. As the high‐resolution structure of the toxic Aβaggregate is unknown, rational design of small molecule inhibitors is not possible, and inhibitors are best isolated by high‐throughput screening. We applied high‐throughput screening to a collection of 65 000 compounds to identify compoundD737as an inhibitor of Aβaggregation.D737diminished the formation of oligomers and fibrils, and reduced Aβ42‐induced cytotoxicity. Most importantly,D737increased the life span and locomotive ability of transgenic flies in a Drosophila melanogaster model of Alzheimer's disease (J Biol Chem, 287, 2012, 38992). To explore the chemical features that makeD737an effective inhibitor of Aβ42 aggregation and toxicity, we tested a small collection of eleven analogues ofD737. Overall, the ability of a compound to inhibit Aβaggregation was a good predictor of its efficacy in prolonging the life span and locomotive ability of transgenic flies expressing human Aβ42 in the central nervous system. Two compounds (D744andD830) with fluorine substitutions on an aromatic ring were effective inhibitors of Aβ42 aggregation and increased the longevity of transgenic flies beyond that observed for the parent compound,D737.
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影响因子：
21.8
作者：
通讯作者：
--
影响因子：
15
作者：
Chen J;Armstrong AH;Koehler AN;Hecht MH
通讯作者：
Hecht MH
影响因子：
2.9
作者：
Petkova, AT;Yau, WM;Tycko, R
通讯作者：
Tycko, R
DOI：
10.1073/pnas.262663499
发表时间：
2002-12-24
影响因子：
11.1
作者：
Petkova, AT;Ishii, Y;Tycko, R
通讯作者：
Tycko, R
影响因子：
2.9
作者：
Necula, Mihaela;Breydo, Leonid;Glabe, Charles G.
通讯作者：
Glabe, Charles G.