Alzheimer’s disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit Aβ aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B’s clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin’s mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both Aβ monomers and oligomers and evidence that silybin may shield the “toxic” surfaces formed by the N-terminal and central hydrophobic regions of Aβ. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin’s therapeutic potential.

中文翻译：

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海藻糖结合物水飞蓟宾为靶向有毒Aβ聚集体的前药。

阿尔茨海默氏病（AD）与淀粉样β肽（Aβ）聚集在大脑中的异常积累有关。水飞蓟素B是从水飞蓟（Silybum marianum）中提取的天然化合物，已显示在体外显着抑制Aβ聚集并在体内发挥神经保护作用。但是，目前对水飞蓟宾B的临床潜力的进一步探索受到三个主要因素的限制：（a）溶解度差，（b）血清不稳定，以及（c）对水飞蓟宾的作用机理只有部分了解。在这里，我们解决了这三个限制。我们证明，将海藻糖部分结合到水飞蓟宾上可显着增加水溶性和在血清中的稳定性，而不会显着损害其抗聚集特性。此外，结合使用具有不同空间分辨率的生物物理技术（即TEM，ThT荧光，CD和NMR光谱），我们分析了海藻糖缀合物与Aβ单体和低聚物的相互作用，并证明水飞蓟宾可能屏蔽了“毒性由Aβ的N端和中央疏水区域形成的表面。最后，水飞蓟宾B（水飞蓟宾B的活性较低）的非对映异构体水飞蓟宾A的比较分析显示，即使化学结构的细微差异也可能对淀粉样蛋白的抑制产生不同的影响。预期对水飞蓟宾作为聚集抑制剂的作用机理的见解将有助于水飞蓟宾的治疗潜力的进一步研究。