5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation.
5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation.
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DOI：
10.1021/acsomega.3c02668
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发表时间：
2023-06-06
期刊：
影响因子：
4.1
通讯作者：
Fortin JS
中科院分区：
文献类型：
--
作者：
Ramirez E;Ganegamage SK;Elbatrawy AA;Alnakhala H;Shimanaka K;Tripathi A;Min S;Rochet JC;Dettmer U;Fortin JS
蛋白质错误折叠会导致大量已知疾病，如阿尔茨海默病、帕金森氏病、亨廷顿病、与甲状腺激素相关的淀粉样变性、2型糖尿病、路易体痴呆和海绵状脑病。为了提供多样化的能够减少蛋白质错误折叠的治疗性小分子组合，我们评估了一组13种化合物：4-(苯并[d]噻唑-2-基)苯胺(BTA)及其含有尿素(1)、硫脲(2)、磺胺(3)、三氮唑(4)和三嗪(5)连接体的衍生物。此外，我们还探索了一种非常有效的反寡聚体5-硝基-1，2-苯并噻唑-3-胺(5-NBA)(化合物6-13)的微小修饰。本研究旨在通过不同的生物物理方法确定BTA及其衍生物对多种易聚集的蛋白质的活性，如转甲状腺激素(TTR81-127，TTR101-125)、α-突触核蛋白(α-SYN)和tau异构体2N4R(Tau 2N4R)。用硫代黄素T(THT)荧光分析法检测BTA及其衍生物处理后上述蛋白质的纤维形成情况。用透射电子显微镜(TEM)证实了其抗纤维活性。利用光反应交联法(PICUP)检测了反寡聚体的活性，确定了5-NBA(低微摩尔浓度)和化合物13(高浓度)是最有希望减少齐聚的化合物。使用表达包涵体倾向αS-3K：：YFP的M17D神经母细胞瘤细胞，基于细胞的分析，5-nABA和NOT BTA抑制了包涵体的形成。5-NBA以剂量依赖的方式抑制原纤维、低聚物和包裹体的形成。5-NBA衍生物可能是减轻蛋白质聚集的关键。在未来，这项研究的结果将提供一个初步的平台，以产生更有效的α-SYN和tau 2N4R齐聚物和纤维形成的抑制剂。
Protein misfolding results in a plethora of known diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic small molecules with the ability to reduce protein misfolding, we evaluated a set of 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) and its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), and triazine (5) linker. In addition, we explored small modifications on a very potent antioligomer 5-nitro-1,2-benzothiazol-3-amine (5-NBA) (compounds 6–13). This study aims to define the activity of BTA and its derivatives on a variety of prone-to-aggregate proteins such as transthyretin (TTR81–127, TTR101–125), α-synuclein (α-syn), and tau isoform 2N4R (tau 2N4R) through various biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation of the previously mentioned proteins after treatment with BTA and its derivatives. Antifibrillary activity was confirmed using transmission electron microscopy (TEM). Photoreactive cross-linking assay (PICUP) was utilized to detect antioligomer activity and lead to the identification of 5-NBA (at low micromolar concentration) and compound 13 (at high concentration) as the most promising in reducing oligomerization. 5-NBA and not BTA inhibited the inclusion formation based on the cell-based assay using M17D neuroblastoma cells that express inclusion-prone αS-3K::YFP. 5-NBA abrogated the fibril, oligomer, and inclusion formation in a dose-dependent manner. 5-NBA derivatives could be the key to mitigate protein aggregation. In the future, the results made from this study will provide an initial platform to generate more potent inhibitors of α-syn and tau 2N4R oligomer and fibril formation.
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影响因子：
3.7
作者：
Koike H;Katsuno M
通讯作者：
Katsuno M
影响因子：
4.1
作者：
Hroch, Lukas;Aitken, Laura;Musilek, Kamil
通讯作者：
Musilek, Kamil
影响因子：
7
作者：
Braak, H;Braak, E
通讯作者：
Braak, E
DOI：
10.1080/13506129.2022.2147636
发表时间：
2022-11-23
影响因子：
5.5
作者：
Buxbaum, Joel N.;Dispenzieri, Angela;Westermark, Per
通讯作者：
Westermark, Per
影响因子：
11
作者：
Hampel H;Hardy J;Blennow K;Chen C;Perry G;Kim SH;Villemagne VL;Aisen P;Vendruscolo M;Iwatsubo T;Masters CL;Cho M;Lannfelt L;Cummings JL;Vergallo A
通讯作者：
Vergallo A