Verbascoside and echinacoside inhibits the fibrillation of human α-synuclein and disassembles mature fibrils.

Targeting α-synuclein (α-syn) amyloid fibrils is considered a promising therapeutic strategy for Parkinson's disease (PD). In this study, we systematically evaluated the direct regulatory effects of two polyphenolic small molecules, Echinacoside (ECH) and Verbascoside (VER), on the amyloidogenesis of human α-syn. A combination of Thioflavin T (ThT) fluorescence kinetics, secondary-structure analyses (CD and FTIR spectroscopy), morphological characterization (TEM, AFM, and DLS), and molecular docking was employed to comprehensively assess their abilities to inhibit α-syn fibril formation and to disassemble preformed fibrils. Both ECH and VER inhibited α-syn fibrillation and promoted the disassembly of mature fibrils in a dose-dependent manner, and alleviated the cytotoxic effects of mature α-syn fibrils on SH-SY5Y cells. Molecular docking analysis revealed that VER preferentially associates with the hydrophobic NAC core of α-syn through multiple non-covalent interactions, thereby stabilizing its binding to amyloid fibrils. Collectively, these findings demonstrate that the phenylethanoid glycosides VER and ECH can directly interfere with α-syn amyloidogenesis, providing experimental support for the development of α-syn-targeted therapeutic strategies for Parkinson's disease.