Inhibition of Insulin Amyloid Fibrillation by the Putative Anticancer Alkaloid Chelerythrine: Spectroscopic, Imaging, and Theoretical Investigations.

Abstract

Type-2 diabetes (T2D) is a major issue in the public health sector due to its high incidence and lack of global therapeutic options. The self-assembly behavior of human insulin (INS) can lead to membrane damage and cell dysfunction, which is directly linked to T2D ailment. The development of a potential therapeutic that can prevent the formation of amyloid fibrils is a promising strategy for the treatment of T2D ailment. Herein, we have used a natural alkaloid, chelerythrine, and explored its antiamyloidogenic function against INS fibrillation. Thioflavin T fluorescence and Congo red absorbance analysis revealed that chelerythrine can significantly suppress the INS fibrillation process. Circular dichroism and FTIR studies demonstrated that chelerythrine markedly reduced the β-sheet content of the INS fibrillar samples, indicating that chelerythrine inhibited the fibrillogenesis process. Tyrosine fluorescence analysis, Nile red analysis, and 8-anilino-1-napthalenesulfonic acid analysis also revealed that chelerythrine arrested the INS fibrillation, and the hydrophobic interaction between INS and chelerythrine played a critical role in this inhibitory process. Apart from the hydrophobic interaction, polar interaction and some other interactions may also be responsible for the inhibitory action of chelerythrine, which was revealed from molecular docking results. AFM imaging analysis strongly supported that the quantity of fibrils in the presence of chelerythrine was markedly less. Furthermore, chelerythrine has the potential to defibrillate existing fibrillar assemblies. Our work clearly elaborated the inhibitory effect of chelerythrine on INS fibrillation.