Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer's Disease and Related Disorders.
Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer's Disease and Related Disorders.
复制标题
托芬那酸衍生物：一类新的转录调节剂，对阿尔茨海默病和相关疾病具有潜在的治疗应用。
DOI：
10.3390/ijms242015216
复制
发表时间：
2023-10-16
影响因子：
5.6
通讯作者：
Zawia NH
中科院分区：
文献类型：
--
作者：
Hill J;Shalaby KE;Bihaqi SW;Alansi BH;Barlock B;Parang K;Thompson R;Ouararhni K;Zawia NH
阿尔茨海默病（AD）领域最近在疾病修饰生物制剂和诊断标志物的开发方面取得了突破。虽然免疫干预提供了期待已久的解决方案，但基于核酸的工具代表了其他干预途径;然而，这些方法成本高且具有侵入性，并且具有严重的副作用。在AD动物模型中，我们已经发现托芬那酸（TA）可以降低AD相关基因及其产物的表达，从而减轻病理负担，改善认知功能。使用TA作为支架和SP1的锌指结构域作为药效团，我们开发了更安全和更有效的脑穿透类似物，其干扰转录起始位点的序列特异性DNA结合，并主要调节SP1靶基因的表达。更重要的是，经处理的细胞的蛋白质组显示约75%的下调产物为SP1靶标。SP1驱动基因和AD生物标志物（如淀粉样前体蛋白（APP）和Tau蛋白）的特定水平也降低，作为这种靶向全身反应的一部分。因此，这些小分子通过干扰淀粉样蛋白和Tau途径，以有限的脱靶系统变化，为实现所需的治疗结果提供了可行的替代方案。
The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.
登录
查看更多内容
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
DOI：
10.1242/dev.106054
发表时间：
2014-06
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Gilmour J;Assi SA;Jaegle U;Kulu D;van de Werken H;Clarke D;Westhead DR;Philipsen S;Bonifer C
通讯作者：
Bonifer C
影响因子：
6
作者：
Hill J;Zawia NH
通讯作者：
Zawia NH
影响因子：
4.6
作者：
Estella, C;Rieckhof, G;Morata, G
通讯作者：
Morata, G