Inhibition of tau amyloid formation and disruption of its preformed fibrils by Naphthoquinone–Dopamine hybrid

Misfolding and aggregation of tau protein, into pathological amyloids, are hallmarks a group neurodegenerative diseases collectively termed tauopathies their modulation may be therapeutically valuable. Herein, we describe the synthesis characterization dopamine-based hybrid molecule, naphthoquinone–dopamine (NQDA). Using thioflavin S assay, CD, transmission electron microscopy, dynamic light scattering, Congo Red birefringence, large unilamellar vesicle leakage assays, demonstrated its efficacy in inhibiting vitro key tau-derived amyloidogenic fragments, PHF6 (VQIVYK) PHF6* (VQIINK), prime drivers full-length disease pathology. Isothermal titration calorimetry analysis revealed that interaction between NQDA is spontaneous has significant binding efficiency driven by both entropic enthalpic processes. Furthermore, efficiently disassembled preformed fibrils nontoxic species. Molecular simulations supported results provided plausible mode with fibril. was also capable protein disrupting dose-dependent manner. In comparative study, IC50 value (50% inhibition fibril formation) (25 µm) ~ 17 µm, which lower than for other bona fide amyloid inhibitors, naphthoquinone-tryptophan, rosmarinic acid, epigallocatechin gallate, 21, 77, or 19 respectively. Comparable superiority observed PHF6*. These findings suggest can useful scaffold designing new therapeutics Alzheimer's tauopathies.