Department of Chemistry, Indian Institute of Technology, Roorkee 247667, India.
Department of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India.
Int J Biol Macromol. 2023 Jun 1;239:124197. doi: 10.1016/j.ijbiomac.2023.124197. Epub 2023 Mar 25.
Misfolding and protein aggregation have been linked to numerous human neurodegenerative disorders such as Alzheimer's, prion, and Parkinson's diseases. Ruthenium (Ru) complexes have received considerable attention in studying protein aggregation due to their interesting photophysical and photo properties. In this study, we have synthesized the novel Ru complexes ([Ru(p-cymene)Cl(L-1)]PF, and [Ru(p-cymene)Cl(L-2)]PF) and investigated their inhibitory activity against the bovine serum albumin (BSA) aggregation and the Aβ peptides amyloid formation. Several spectroscopic methods were used to characterize these complexes, and the molecular structure of the complex was determined by X-ray crystallography. Amyloid aggregation and inhibition activities were examined using the Thioflavin-T (ThT) assay, and the secondary structures of the protein were analyzed by circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The cell viability assay was carried out on the neuroblastoma cell line, revealing that the complex Ru-2 showed better protective effects against Aβ peptide toxicity on neuro-2a cells than the complex Ru-1. Molecular docking studies elucidate the binding sites and interactions between the Ru-complexes and Aβ peptides. The experimental studies revealed that these complexes significantly inhibited the BSA aggregation and Aβ amyloid fibril formation at 1:3 and 1:1 molar concentrations, respectively. Antioxidant assays demonstrated that these complexes act as antioxidants, protecting from amyloid-induced oxidative stress. Molecular docking studies with the monomeric Aβ (PDB: 1IYT) show hydrophobic interaction, and both complexes bind preferably in the central region of the peptide and coordinate with two binding sites of the peptide. Hence, we suggest that the Ru-based complexes could be applied as a potential agent in metallopharmaceutical research against Alzheimer's disease.
错误折叠和蛋白质聚集与许多人类神经退行性疾病有关，如阿尔茨海默病、朊病毒和帕金森病。由于其有趣的光物理和光性质，钌（Ru）配合物在研究蛋白质聚集方面受到了广泛关注。在这项研究中，我们合成了新型 Ru 配合物([Ru(p-cymene)Cl(L-1)]PF和[Ru(p-cymene)Cl(L-2)]PF)，并研究了它们对牛血清白蛋白(BSA)聚集和 Aβ肽淀粉样形成的抑制活性。使用几种光谱方法对这些配合物进行了表征，并通过 X 射线晶体学确定了配合物的分子结构。使用硫黄素-T(ThT)测定法检查了淀粉样蛋白聚集和抑制活性，并通过圆二色性(CD)光谱法和透射电子显微镜(TEM)分析了蛋白质的二级结构。在神经母细胞瘤细胞系上进行了细胞活力测定，结果表明配合物 Ru-2 对 Aβ 肽毒性对神经-2a 细胞的保护作用优于配合物 Ru-1。分子对接研究阐明了 Ru-复合物与 Aβ 肽之间的结合位点和相互作用。实验研究表明，这些配合物在 1:3 和 1:1 摩尔浓度下分别显著抑制 BSA 聚集和 Aβ 淀粉样纤维形成。抗氧化测定表明，这些配合物作为抗氧化剂发挥作用，可防止淀粉样诱导的氧化应激。与单体 Aβ(PDB:1IYT)的分子对接研究表明存在疏水相互作用，并且两个配合物都优选结合在肽的中心区域，并与肽的两个结合位点配位。因此，我们认为基于 Ru 的配合物可作为治疗阿尔茨海默病的金属药物研究中的潜在药物。
