Targeting Pathological Tau by Small Molecule Inhibition of the Poly(A):MSUT2 RNA-Protein Interaction.
Targeting Pathological Tau by Small Molecule Inhibition of the Poly(A):MSUT2 RNA-Protein Interaction.
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DOI：
10.1021/acschemneuro.0c00214
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发表时间：
2020-08-05
影响因子：
5
通讯作者：
Kraemer BC
中科院分区：
文献类型：
--
作者：
Baker JD;Uhrich RL;Strovas TJ;Saxton AD;Kraemer BC
由异常聚集的tau蛋白组成的神经原纤维缠结是阿尔茨海默病和相关痴呆症的标志。最近的研究表明，哺乳动物Tau病抑制因子2(MSUT2)，也被称为ZC3H14(锌指CCCH-Type包含14)，控制着病理性Tau在培养的人类细胞和小鼠中的积累。敲除MSUT2基因可以保护神经元免受神经退行性变态反应的影响，并保护学习和记忆。MSUT2蛋白通过其C端CCCH型锌指结构域结合mRNA的多聚腺苷[PolyA]尾部，CCCH结构域功能的丧失抑制了秀丽线虫和小鼠的肌萎缩症。因此，我们假设，抑制Poly(A)：MSUT2 RNA与蛋白质的相互作用将改善病理性tau的积累。在这里，我们提出了一种高通量筛选方法，用于鉴定抑制聚(A)：MSUT2 RNA-蛋白质相互作用的小分子。我们使用荧光偏振分析进行初始的小分子发现，目的是为了重新利用从NIH临床资料(NIHCC)中确定的HITS。我们的药物再利用开发工作流程包括通过剂量反应分析、特异性测试、活性和细胞毒性的正交分析对HITS进行验证。通过这个筛选漏斗的经过验证的化合物将在未来的研究中评估翻译效果。这一临床前药物开发流程确定了FDA批准的各种药物度洛西汀、萨奎那韦和氯法齐明作为潜在的再利用候选药物，以减少病理性tau的蓄积。
Neurofibrillary tangles composed of aberrantly aggregating tau protein are a hallmark of Alzheimer’s disease and related dementia disorders. Recent work has shown that mammalian suppressor of tauopathy 2 (MSUT2), also named ZC3H14 (Zinc Finger CCCH-Type Containing 14), controls accumulation of pathological tau in cultured human cells and mice. Knocking out MSUT2 protects neurons from neurodegenerative tauopathy and preserves learning and memory. MSUT2 protein functions to bind polyadenosine [poly(A)] tails of mRNA through its C-terminal CCCH type zinc finger domains, and loss of CCCH domain function suppresses tauopathy in Caenorhabditis elegans and mice. Thus, we hypothesized that inhibiting the poly(A):MSUT2 RNA–protein interaction would ameliorate pathological tau accumulation. Here we present a high-throughput screening method for the identification of small molecules inhibiting the poly(A):MSUT2 RNA–protein interaction. We employed a fluorescent polarization assay for initial small molecule discovery with the intention to repurpose hits identified from the NIH Clinical Collection (NIHCC). Our drug repurposing development workflow included validation of hits by dose–response analysis, specificity testing, orthogonal assays of activity, and cytotoxicity. Validated compounds passing through this screening funnel will be evaluated for translational effectiveness in future studies. This preclinical drug development pipeline identified diverse FDA approved drugs duloxetine, saquinavir, and clofazimine as potential repurposing candidates for reducing pathological tau accumulation.
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影响因子：
16.6
作者：
Malerba A;Klein P;Bachtarzi H;Jarmin SA;Cordova G;Ferry A;Strings V;Espinoza MP;Mamchaoui K;Blumen SC;St Guily JL;Mouly V;Graham M;Butler-Browne G;Suhy DA;Trollet C;Dickson G
通讯作者：
Dickson G
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.5
作者：
Guthrie, Chris R.;Greenup, Lynne;Kraemer, Brian C.
通讯作者：
Kraemer, Brian C.
影响因子：
6.7
作者：
Bellera, Carolina L.;Balcazar, Dario E.;Talevi, Alan
通讯作者：
Talevi, Alan
影响因子：
3.5
作者：
Apponi, Luciano H.;Leung, Sara W.;Pavlath, Grace K.
通讯作者：
Pavlath, Grace K.