Targeting Pathological Tau by Small Molecule Inhibition of the Poly(A):MSUT2 RNA-Protein Interaction.,ACS Chemical Neuroscience

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Targeting Pathological Tau by Small Molecule Inhibition of the Poly(A):MSUT2 RNA-Protein Interaction.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-06-26 , DOI: 10.1021/acschemneuro.0c00214
Jeremy D Baker _{1,

2} , Rikki L Uhrich ₂ , Timothy J Strovas ₂ , Aleen D Saxton ₂ , Brian C Kraemer _{1,

2,

3,

4}

Affiliation

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.

中文翻译：

通过小分子抑制 Poly(A):MSUT2 RNA-蛋白质相互作用来靶向病理性 Tau。

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一个标志。最近的研究表明，哺乳动物 tau 蛋白病抑制因子 2 (MSUT2)，也称为 ZC3H14（含 14 的锌指 CCCH 型），可控制培养的人类细胞和小鼠中病理性 tau 蛋白的积累。敲除MSUT2可保护神经元免受神经退行性 tau 病的影响，并保留学习和记忆。 MSUT2 蛋白通过其 C 端 CCCH 型锌指结构域结合 mRNA 的聚腺苷 [poly(A)] 尾部，CCCH 结构域功能的丧失可抑制秀丽隐杆线虫和小鼠的 tau 蛋白病。因此，我们假设抑制 Poly(A):MSUT2 RNA-蛋白质相互作用将改善病理性 tau 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 Poly(A):MSUT2 RNA-蛋白质相互作用的小分子。我们采用荧光偏振测定来进行最初的小分子发现，目的是重新利用从 NIH 临床收藏 (NIHCC) 中鉴定出的命中化合物。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、活性正交测定和细胞毒性来验证命中。通过该筛选漏斗的经过验证的化合物将在未来的研究中评估其转化有效性。该临床前药物开发管道确定了 FDA 批准的多种药物度洛西汀、沙奎那韦和氯法齐明作为减少病理性 tau 积累的潜在再利用候选药物。

更新日期：2020-08-05

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