State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy . China Pharmaceutical University , Nanjing 210009 , People's Republic of China.
Institute of Traditional Chinese Medicine & Natural Products , Jinan University , Guangzhou 510632 , People's Republic of China.
ACS Chem Neurosci. 2019 Feb 20;10(2):996-1007. doi: 10.1021/acschemneuro.8b00252. Epub 2018 Jul 6.
Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer's disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (-)-1, (+)-2, and (-)-2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3β (Ser9) and decrease the expressions of p-GSK-3β (Tyr216) and p-GSK-3β (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)-2 and (-)-2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.
糖原合酶激酶-3β（GSK-3β）是过度磷酸化 tau 蛋白的关键酶，是阿尔茨海默病（AD）的有前途的治疗靶点。在这里，我们首次报道，五味子素 B（Sch B）的立体异构体（+）-1、（-）-1、（+）-2 和（-）-2，是有效的 GSK-3β 抑制剂。它们被证明以正位结合模式选择性地靶向 GSK-3β，IC 值分别为 340、290、80 和 70 nM。进一步的研究表明，这些立体异构体可以显著增加 p-GSK-3β（Ser9）的表达，并降低 p-GSK-3β（Tyr216）和 p-GSK-3β（Tyr279）的表达。最后，这些化合物可以减轻 Aβ诱导的细胞损伤和 AD 小鼠的认知障碍，特别是（+）-2 和（-）-2。总之，Sch B 的立体异构体，特别是（+）-2 和（-）-2，被发现是潜在的选择性 ATP 竞争性 GSK-3β 抑制剂，这进一步影响了它们的抗 AD 作用。这些有希望的发现解释了 Sch B 在 AD 中的生物学靶点，并为 Sch B 的立体化学和生物活性带来了新的认识。
