C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies

These data illustrates the capacitity of a family of C-glycosides to enhance and activate protein phosphatase 2A (PP2A). This enzyme is an important Ser/Thr phosphatase that participates in the regulation of multiple cellular processes, and its deficient activity of PP2A has been involved in the etiology of various diseases. The C-glycosides presented in this set of data are analogues to the central fragment of the toxin okadaic acid, which selectively inhibits PP2A. Chemical design aimed to turn the pharmalogical activity in a PP2A-activating profile. In order to probe our hypothesis, these compounds were tested in pharmacological models of Alzheimer's disease (AD). Depression of PP2A has been widely corroborated in AD, where the resulting manifestation is the hyperphosphorylation of several PP2A substrates, such as tau protein. Indeed, one of the main histopathological features of AD are neurofibrillary tangles, formed by hyperphosphorylated tau protein. Therefore, data herein deposited show: 1) recovery of phosphatase activity by the described compounds in a scenario of PP2A depression defined by administration of either okadaic acid or cytostatin (a milder PP2A inhibitor but much more selective), monitored by the pNPP method: files "pNPP vs..." 2) protection of neuroblatoma cultures and cortical neurons exerted by compounds in presence of several toxic stimuli related to neurodegeneration (okadaic acid, cytostatin, rotenone plus oligomycin A or glutamate) measured by MTT method: files "Protection vs ..." 3) effect of the best PP2A-activating compound (10) on the PP2A activity of two diferent trimeric complexes, namely B55alpha and B56alfa, measured by the malachite green method: file "Malachite of 10 vs OA by Arribas et al" 4) effect of 10 on the expression of PP2A phosphoprotein substrates in presence of okadaic acid: files "WB of ..." 5) computational docking of compound 10 at its binding site in PP2A-AC dimer: files "Docking of most stable 10 at PP2A" 6) study of the CNS penetration of compound 10 by PAMPA: file "PAMPA of 10 by Arribas et al" 7) in vivo studies of the effect of 10 on the memory deficit exacerbated by LPS in mice, measured by the object recognition test: file "ORT of 10 vs LPS by Arribas et al" These promising experimental data, centered on profiling the lead compound ITH12711 (10)(X ray data also deposited as cif file and crystal structure report", would validate our rational approach to design new PP2A-activating drugs based on OA central fragment.本数据集展示了一系列C-糖苷（C-glycosides）增强并激活蛋白磷酸酶2A（protein phosphatase 2A，PP2A）的能力。该酶是一类重要的丝氨酸/苏氨酸（serine/threonine，Ser/Thr）磷酸酶，参与调控多种细胞进程，而PP2A活性缺失与多种疾病的发病机制密切相关。 本数据集收录的C-糖苷类化合物为毒素冈田酸（okadaic acid）核心片段的类似物，而冈田酸本身可选择性抑制PP2A活性。本研究通过化学设计，将该类化合物的药理活性改造为PP2A激活型。为验证我们的假说，研究团队在阿尔茨海默病（Alzheimer's disease，AD）药理模型中对这些化合物进行了测试。AD患者体内普遍存在PP2A活性抑制的情况，由此引发的结果是多种PP2A底物（如tau蛋白）的过度磷酸化。事实上，阿尔茨海默病的主要病理特征之一即为过度磷酸化tau蛋白聚集形成的神经原纤维缠结。 因此，本数据集收录的实验数据如下： 1. 通过pNPP法检测：在通过注射冈田酸或细胞抑素（cytostatin，一种温和但选择性更强的PP2A抑制剂）构建的PP2A活性抑制模型中，本研究所述化合物可恢复磷酸酶活性，对应数据文件为"pNPP vs..." 2. 通过MTT法检测：在多种神经退行性相关毒性刺激（冈田酸、细胞抑素、鱼藤酮联合寡霉素A或谷氨酸）存在的环境中，化合物可对神经母细胞瘤（neuroblastoma）培养物及皮层神经元起到保护作用，对应数据文件为"Protection vs ..." 3. 通过孔雀石绿法检测：最优PP2A激活化合物（10号）对两种不同三聚体复合物（即B55α与B56α）的PP2A活性的影响，对应数据文件为"Malachite of 10 vs OA by Arribas et al" 4. 通过免疫印迹（Western Blot，WB）法检测：10号化合物在冈田酸存在下对PP2A磷酸化底物蛋白表达的影响，对应数据文件为"WB of ..." 5. 化合物10在PP2A-AC二聚体结合位点的计算机分子对接结果，对应数据文件为"Docking of most stable 10 at PP2A" 6. 采用平行人工膜渗透模型（parallel artificial membrane permeability assay，PAMPA）检测的10号化合物中枢神经系统穿透性研究结果，对应数据文件为"PAMPA of 10 by Arribas et al" 7. 通过物体识别实验（object recognition test，ORT）检测的10号化合物对脂多糖（lipopolysaccharide，LPS）诱导的小鼠记忆损伤的改善作用的体内研究结果，对应数据文件为"ORT of 10 vs LPS by Arribas et al" 本研究以先导化合物ITH12711（即10号化合物）为核心的一系列极具潜力的实验数据（其X射线衍射数据亦以cif文件及晶体结构报告形式收录），将验证我们基于冈田酸核心片段设计新型PP2A激活药物的理性设计策略的可行性。