Department of Chemistry, Renmin University of China, Beijing, 100872, China.
J Mater Chem B. 2022 Jun 22;10(24):4650-4661. doi: 10.1039/d2tb00230b.
Biflavones are a kind of natural compound with a variety of biological activities, which have the capability of reversing diabetes and neurodegenerative diseases. The human islet amyloid polypeptide (hIAPP) is closely related to the pathological process of type II diabetes mellitus (T2DM). The development of new inhibitors is crucial to prevent hIAPP aggregation against T2DM. However, the influences of biflavones on hIAPP aggregation are unknown. In this work, we utilized a series of biophysical and biochemical techniques to seek the inhibitory effects of two biflavones on hIAPP fibril formation and their interaction mechanism. The biflavones namely amentoflavone (1), and bilobetin (2), distinctly prevented the self-assembly behavior of hIAPP, and depolymerized the aged aggregates to small oligomers and monomers. In addition, the two compounds displayed strong binding affinity to hIAPP mainly through hydrophobic and hydrogen bonding interactions, and the hydroxyl substitution in 1 was superior to the methoxy substitution in 2 at the same C8 position in impeding hIAPP aggregation. 1 and 2 also decreased hIAPP-induced cytotoxicity by reducing peptide oligomerization. This work offers useful data for understanding the roles of biflavones in hIAPP fibrillation and for the treatment of T2DM and other amyloidosis related diseases.
双黄酮是一类具有多种生物活性的天然化合物，具有逆转糖尿病和神经退行性疾病的能力。人胰岛淀粉样多肽（hIAPP）与 2 型糖尿病（T2DM）的病理过程密切相关。开发新的抑制剂对于预防 hIAPP 聚集以对抗 T2DM 至关重要。然而，双黄酮对 hIAPP 聚集的影响尚不清楚。在这项工作中，我们利用一系列生物物理和生化技术来研究两种双黄酮对 hIAPP 纤维形成的抑制作用及其相互作用机制。这两种双黄酮，即穗花杉双黄酮（1）和银杏双黄酮（2），明显阻止了 hIAPP 的自组装行为，并将老化的聚集体解聚为小寡聚物和单体。此外，这两种化合物与 hIAPP 具有很强的结合亲和力，主要通过疏水和氢键相互作用，而 1 中在 C8 位的羟基取代比 2 中在同一 C8 位的甲氧基取代更能阻止 hIAPP 聚集。1 和 2 还通过减少肽寡聚化来降低 hIAPP 诱导的细胞毒性。这项工作为理解双黄酮在 hIAPP 纤维形成中的作用以及治疗 T2DM 和其他淀粉样变性相关疾病提供了有用的数据。
