Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of τ aggregation and toxicity in vitro and in cells
Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of τ aggregation and toxicity in vitro and in cells
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DOI：
10.1021/bi700878g
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发表时间：
2007-09-04
期刊：
影响因子：
2.9
通讯作者：
Mandelkow, Eckhard
中科院分区：
文献类型：
--
作者：
Pickhardt, Marcus;Larbig, Gregor;Mandelkow, Eckhard
阿尔茨海默病的关键病理特征之一是tau蛋白的聚集。因此，我们正在寻找能够抑制该反应的化合物。基于 200000 种化合物的初步筛选 [Pickhardt, M.、Gazova, Z.、von Bergen, M.、Khlistunova, I.、Wang, Y.、Hascher, A.、Mandelkow, E. M.、Biernat, J. 和 Mandelkow, E. (2005) 蒽醌抑制 tau 聚集并溶解阿尔茨海默病的成对螺旋丝 体外和细胞内，J. Biol。化学。 280, 3628-3635]，我们进行了计算机筛选，并预测一种新的苯基噻唑基酰肼 (PTH) 化合物可能会成为热门药物 [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., 和 Mandelkow, E. (2007) Screening forhibitors of tau 蛋白聚集成阿尔茨海默配对螺旋 细丝：基于配体的方法可成功实现支架跳跃。电流。阿尔茨海默研究中心。 4 (3), 315-323.]。该化合物的合成表明，它确实具有抑制 tau 从头聚集和分解预先形成的聚集体的活性（IC50 = 7.7 μM 和 DC50 = 10.8 μM）。我们现在已经合成了 49 个相似的结构，并确定了 PTH 的核心对于活性至关重要，因此代表了先导结构。通过饱和转移差核磁共振对结合表位的分析表明，tau 蛋白与抑制剂芳香区域的配体之间存在强烈的相互作用。通过核心的化学变化，我们将抑制效力提高了五倍。根据 tau 聚集的 N2A 细胞模型判断，这些化合物显示出低毒性，适合进一步开发。
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 mu M and DC50 = 10.8 mu M). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development.