In:
The FEBS Journal, Wiley, Vol. 288, No. 14 ( 2021-07), p. 4267-4290
Abstract:
Misfolding and aggregation of tau protein, into pathological amyloids, are hallmarks of a group of neurodegenerative diseases collectively termed tauopathies and their modulation may be therapeutically valuable. Herein, we describe the synthesis and characterization of a dopamine‐based hybrid molecule, naphthoquinone–dopamine (NQDA). Using thioflavin S assay, CD, transmission electron microscopy, dynamic light scattering, Congo Red birefringence, and large unilamellar vesicle leakage assays, we demonstrated its efficacy in inhibiting the in vitro aggregation of key tau‐derived amyloidogenic fragments, PHF6 (VQIVYK) and PHF6* (VQIINK), prime drivers of aggregation of full‐length tau in disease pathology. Isothermal titration calorimetry analysis revealed that the interaction between NQDA and PHF6 is spontaneous and has significant binding efficiency driven by both entropic and enthalpic processes. Furthermore, NQDA efficiently disassembled preformed fibrils of PHF6 and PHF6* into nontoxic species. Molecular dynamic simulations supported the in vitro results and provided a plausible mode of binding of NQDA with PHF6 fibril. NQDA was also capable of inhibiting the aggregation of full‐length tau protein and disrupting its preformed fibrils in vitro in a dose‐dependent manner. In a comparative study, the IC 50 value (50% inhibition of fibril formation) of NQDA in inhibiting the aggregation of PHF6 (25 µ m ) was ~ 17 µ m , which is lower than for other bona fide amyloid inhibitors, naphthoquinone‐tryptophan, rosmarinic acid, epigallocatechin gallate, ~ 21, ~ 77, or ~ 19 µ m , respectively. Comparable superiority of NQDA was observed for inhibition of PHF6*. These findings suggest that NQDA can be a useful scaffold for designing new therapeutics for Alzheimer's disease and other tauopathies.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/febs.v288.14
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2172518-4
SSG:
12
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