State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
Quzhou Institute for Innovation in Resource Chemical Engineering, Quzhou, Zhejiang Province 324000, P. R. China.
ACS Appl Mater Interfaces. 2023 Jul 26;15(29):34497-34504. doi: 10.1021/acsami.3c04969. Epub 2023 Jul 13.
Prion disorders are a group of lethal infectious neurodegenerative diseases caused by the spontaneous aggregation of misfolded prion proteins (PrP). The oxidation of such proteins by chemical reagents can significantly modulate their aggregation behavior. Herein, we exploit a series of vanadium-substituted Keggin-type tungsten and molybdenum POMs (W- and Mo-POMs) as chemical tools to oxidize PrP106-126 (denoted as PrP), an ideal model for studying PrP. Due to the band gaps being larger than that of Mo-POMs, W-POMs possess higher structural stability and show stronger binding and oxidation effect on PrP. Additionally, the substitution of W/Mo by vanadium elevates the local electron distribution on the bridged O(26) atom, thereby strengthening the hydrogen bonding of POMs with the histidine site. Most importantly, with the number of substituted vanadium increases, the LUMO energy level of POMs decreases, making it easier to accept electrons from methionine. As a result, PWV displays the strongest oxidation on the methionine residue of PrP, leading to an excellent inhibitory effect on PrP aggregation and a significant attenuation on its neurotoxicity.
朊病毒疾病是一组由错误折叠的朊病毒蛋白（PrP）自发聚集引起的致命传染性神经退行性疾病。化学试剂对这些蛋白质的氧化可以显著调节它们的聚集行为。在此，我们利用一系列钒取代的 Keggin 型钨和钼多金属氧酸盐（W 和 Mo-POMs）作为化学工具来氧化 PrP106-126（表示为 PrP），这是研究 PrP 的理想模型。由于带隙大于 Mo-POMs，W-POMs 具有更高的结构稳定性，并对 PrP 表现出更强的结合和氧化作用。此外，钒取代 W/Mo 会增加桥接 O(26)原子上的局部电子分布，从而增强 POMs 与组氨酸位点的氢键。最重要的是，随着取代的钒数量的增加，POMs 的最低未占分子轨道（LUMO）能级降低，使其更容易从蛋氨酸中接受电子。结果，PWV 对 PrP 的蛋氨酸残基表现出最强的氧化作用，对 PrP 聚集具有极好的抑制作用，并显著减弱其神经毒性。
