Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease.
Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease.
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DOI：
10.4155/fmc.11.47
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发表时间：
2011-05
影响因子：
4.2
通讯作者：
Stock JB
中科院分区：
文献类型：
--
作者：
Voronkov M;Braithwaite SP;Stock JB
Tau过度磷酸化被认为通过促进神经原纤维缠结的形成在阿尔茨海默病的病因学中发挥重要作用。因此，通过激酶抑制降低磷酸化已成为药物开发的目标，但尽管在开发治疗性激酶抑制剂方面付出了相当大的努力，但成功仍然有限。另一种方法是开发药物来增强主要的磷酸tau磷酸酶，磷酸蛋白磷酸酶2A （PP2A）的活性。在本文中，我们回顾了该机制在药理学上可行的证据，并有望提供下一代阿尔茨海默病治疗方法。据报道，许多不同的化学型通过一系列提出的机制导致PP2A活性增强。这些化合物中的一些似乎直接作为PP2A的变张激活剂，而另一些则通过抑制PP2A抑制剂的结合或通过改变翻译后修饰间接起作用，这些修饰反过来调节PP2A对磷酸化tau的活性。这些结果表明，PP2A可能提供一个有用的靶点，可以通过药物干预安全、选择性和有效地调节，以治疗阿尔茨海默病。
Tau hyperphosphorylation is thought to play an important role in the etiology of Alzheimer’s disease by facilitating the formation of neurofibrillary tangles. Reducing phosphorylation through kinase inhibition has therefore emerged as a target for drug development, but despite considerable efforts to develop therapeutic kinase inhibitors, success has been limited. An alternative approach is to develop pharmaceuticals to enhance the activity of the principal phospho-tau phosphatase, phosphoprotein phosphatase 2A (PP2A). In this article we review evidence that this mechanism is pharmacologically achievable and has promise for delivering the next generation of Alzheimer’s disease therapeutics. A number of different chemotypes have been reported to lead to enhanced PP2A activity through a range of proposed mechanisms. Some of these compounds appear to act directly as allosteric activators of PP2A, while others act indirectly by inhibiting the binding of PP2A inhibitors or by altering post-translational modifications that act in turn to regulate PP2A activity towards phospho-tau. These results indicate that PP2A may provide a useful target that can be safely, selectively and effectively modulated through pharmaceutical intervention to treat Alzheimer’s disease.
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影响因子：
7.3
作者：
Chang E;Congdon EE;Honson NS;Duff KE;Kuret J
通讯作者：
Kuret J
影响因子：
6.1
作者：
Braithwaite SP;Schmid RS;He DN;Sung ML;Cho S;Resnick L;Monaghan MM;Hirst WD;Essrich C;Reinhart PH;Lo DC
通讯作者：
Lo DC
影响因子：
4.8
作者：
Chalfant, CE;Kishikawa, K;Hannun, YA
通讯作者：
Hannun, YA
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
5.5
作者：
Cho, Du-Hyong;Choi, Yoon Jung;Jo, Inho
通讯作者：
Jo, Inho