Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel.
Department of Biological Engineering, Indian Institute of Technology, Gandhinagar, Palaj, Gandhinagar, Gujarat, 382355, India.
Sci Rep. 2018 Jan 8;8(1):71. doi: 10.1038/s41598-017-18443-2.
Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer's disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment.
细胞内的 tau 蛋白缠结和细胞外的 β-淀粉样斑块是阿尔茨海默病 (AD) 的标志，其特征是天然无规的单体蛋白/肽转化为错误折叠的富含 β-折叠的聚集物。因此，抑制聚集级联或拆散预先形成的聚集体成为疾病治疗的关键事件。在本研究中，我们表明萘醌-色氨酸杂合体，即 NQTrp 和 Cl-NQTrp，能够显著破坏 Tau 衍生的 PHF6（VQIVYK）肽和全长 tau 蛋白的预形成纤维状聚集物，这在 ThS 测定、CD 光谱和 TEM 中均可见，且呈剂量依赖性。与萘醌-色氨酸杂合体的 PHF6 低聚物和原纤维的分子动力学模拟提供了一种基于结构-功能的作用机制，突出了在纤维解体过程中疏水相互作用和氢键形成的作用。这些发现表明了 NQTrp 和 Cl-NQTrp 在拆散纤维状聚集物方面的有效性，并可能有助于设计用于 AD 治疗的新型杂合分子。
