1,4-Diurea- and 1,4-Dithiourea-Substituted Aromatic Derivatives Selectively Inhibit α-Synuclein Oligomer Formation In Vitro.
1,4-Diurea- and 1,4-Dithiourea-Substituted Aromatic Derivatives Selectively Inhibit α-Synuclein Oligomer Formation In Vitro.
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DOI：
10.1021/acsomega.3c07453
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发表时间：
2024-01-09
期刊：
影响因子：
4.1
通讯作者：
Fortin, Jessica S.
中科院分区：
文献类型：
--
作者：
Ganegamage, Susantha K.;Ramirez, Eduardo;Alnakhala, Heba;Tripathi, Arati;Nguyen, Cuong Calvin Duc;Zami, Ashique;Ostafe, Raluca;Tian, Shiliang;Dettmer, Ulf;Fortin, Jessica S.
帕金森病（PD）是第二大常见的神经退行性疾病，影响全球老年人群。在PD中，α-突触核蛋白（α-syn）的错误折叠导致在黑质的中脑神经元中形成称为Lewy小体（LB）的包涵体和其他特定的脑定位，这与神经变性相关。没有批准的策略来减少PD患者神经元中LB的形成。我们的药物发现计划集中在脲和硫脲化合物与氨基吲哚部分偶联的合成，以消除α-syn聚集并减缓PD的进展。我们合成了几种具有中心1，4-苯基二脲/硫脲键的脲和硫脲类似物，并评估了它们在减少α-syn聚集方面的有效性，特别关注对其他蛋白质中寡聚体形成的选择性抑制。我们利用生物物理方法，如硫磺素T（ThT）荧光测定，透射电子显微镜（TEM），未修饰蛋白质的光诱导交联（PICUP），以及M17 D细胞内包涵体细胞为基础的测定，以评估我们最好的化合物的抗聚集特性和细胞保护。我们的结果通过ThT测定鉴定化合物1为减少α-syn原纤维形成的最佳化合物。化合物1的反寡聚体形成随后被化合物2取代。两种化合物选择性地减少α-syn的寡聚体形成，但不减少tau 4 R亚型（0 N4 R，2N 4 R）或p-tau（亚型1 N4 R）的寡聚体形成。通过ThT和原子力显微镜观察，化合物1和2未能消除tau 0 N3 R原纤维形成。通过TEM，化合物2在减少重组α-syn原纤维的形成方面最好。与化合物2相反，化合物1以剂量依赖性方式减少M17 D神经母细胞瘤细胞中α-syn包涵体的形成。化合物1可以提供分子支架用于优化对称分子的α-syn抗聚集活性，具有潜在的治疗应用和PD中小分子的开发。
Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting the elderly population worldwide. In PD, the misfolding of α-synuclein (α-syn) results in the formation of inclusions referred to as Lewy bodies (LB) in midbrain neurons of the substantia nigra and other specific brain localizations, which is associated with neurodegeneration. There are no approved strategies to reduce the formation of LB in the neurons of patients with PD. Our drug discovery program focuses on the synthesis of urea and thiourea compounds coupled with aminoindole moieties to abrogate α-syn aggregation and to slow down the progression of PD. We synthesized several urea and thiourea analogues with a central 1,4-phenyl diurea/thiourea linkage and evaluated their effectiveness in reducing α-syn aggregation with a special focus on the selective inhibition of oligomer formation among other proteins. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), as well as M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. Our results identified compound 1 as the best compound in reducing α-syn fibril formation via ThT assays. The antioligomer formation of compound 1 was subsequently superseded by compound 2. Both compounds selectively curtailed the oligomer formation of α-syn but not tau 4R isoforms (0N4R, 2N4R) or p-tau (isoform 1N4R). Compounds 1 and 2 failed to abrogate tau 0N3R fibril formation by ThT and atomic force microscopy. Compound 2 was best at reducing the formation of recombinant α-syn fibrils by TEM. In contrast to compound 2, compound 1 reduced the formation of α-syn inclusions in M17D neuroblastoma cells in a dose-dependent manner. Compound 1 may provide molecular scaffolds for the optimization of symmetric molecules for its α-syn antiaggregation activity with potential therapeutic applications and development of small molecules in PD.
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影响因子：
2.3
作者：
Ramirez, Eduardo;Min, Sehong;Fortin, Jessica S.
通讯作者：
Fortin, Jessica S.
影响因子：
5.1
作者：
Liu M;Sui D;Dexheimer T;Hovde S;Deng X;Wang KW;Lin HL;Chien HT;Kweon HK;Kuo NS;Ayoub CA;Jimenez-Harrison D;Andrews PC;Kwok R;Bochar DA;Kuret J;Fortin J;Tsay YG;Kuo MH
通讯作者：
Kuo MH
帕金森氏病的患病率在北美。
DOI：
10.1038/s41531-018-0058-0
发表时间：
2018
期刊：
NPJ Parkinson's disease
影响因子：
--
作者：
Marras C;Beck JC;Bower JH;Roberts E;Ritz B;Ross GW;Abbott RD;Savica R;Van Den Eeden SK;Willis AW;Tanner CM;Parkinson’s Foundation P4 Group
通讯作者：
Parkinson’s Foundation P4 Group
影响因子：
3
作者：
Maltarollo, Vinicius G.;Honorio, Kathia M.
通讯作者：
Honorio, Kathia M.
影响因子：
--
作者：
Fu, Yi;Zhao, Ji;Chen, Zhiguo
通讯作者：
Chen, Zhiguo