Wang Yanan, Zheng Ting, Huo Yan, Du Weihong
Department of Chemistry, Renmin University of China, Beijing 100872, China.
ACS Chem Neurosci. 2022 Jul 20;13(14):2164-2175. doi: 10.1021/acschemneuro.2c00206. Epub 2022 Jul 7.
Type-2 diabetes mellitus (T2DM) is one of the most concerning public health problems because of its high incidence, multiple complications, and difficult treatment. Human islet amyloid polypeptide (hIAPP) is closely linked to T2DM because its abnormal self-assembly causes membrane damage and cell dysfunction. The development of potential inhibitors to prevent hIAPP fibrillation is a promising strategy for the intervention and treatment of diabetes. Natural isoquinoline alkaloids are used as effective medication that targets different biomolecules. Although studies explored the efficacy of berberine, jatrorrhizine, and chelerythrine in diabetes, the underlying mechanism remains unclear. Herein, three isoquinoline alkaloids are selected to reveal their roles in hIAPP aggregation, disaggregation, and cell protection. All three compounds displayed good inhibitory effects on peptide fibrillation, scattered the preformed fibrils into small oligomers and most monomers, and upregulated cell viability by reducing hIAPP oligomerization. Moreover, combined biophysical analyses indicated that the compounds affected the β-sheet structure and hydrophobicity of polypeptides significantly, and the benzo[]phenanthridine structure of chelerythrine was beneficial to the inhibition of hIAPP aggregation and their hydrophobic interaction, compared with that of berberine and jatrorrhizine. Our work elaborated the effects of these alkaloids on hIAPP fibrillation and reveals a possible mechanism for these compounds against T2DM.
2型糖尿病（T2DM）是最令人担忧的公共卫生问题之一，因其发病率高、并发症多且治疗困难。人胰岛淀粉样多肽（hIAPP）与T2DM密切相关，因为其异常的自组装会导致膜损伤和细胞功能障碍。开发潜在的抑制剂以防止hIAPP纤维化是干预和治疗糖尿病的一种有前景的策略。天然异喹啉生物碱用作针对不同生物分子的有效药物。尽管已有研究探讨了黄连素、药根碱和白屈菜红碱在糖尿病治疗中的疗效，但其潜在机制仍不清楚。在此，选择三种异喹啉生物碱来揭示它们在hIAPP聚集、解聚和细胞保护中的作用。这三种化合物均对肽纤维化表现出良好的抑制作用，将预先形成的纤维分散成小的寡聚体和大多数单体，并通过减少hIAPP寡聚化来上调细胞活力。此外，综合生物物理分析表明，这些化合物显著影响多肽的β-折叠结构和疏水性，与黄连素和药根碱相比，白屈菜红碱中的苯并[]菲啶结构有利于抑制hIAPP聚集及其疏水相互作用。我们的工作阐述了这些生物碱对hIAPP纤维化的影响，并揭示了这些化合物对抗T2DM的可能机制。
