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  • Title: Lysozyme amyloid fibrillization in presence of tacrine/acridone-coumarin heterodimers.
    Author: Ulicna K, Bednarikova Z, Hsu WT, Holztragerova M, Wu JW, Hamulakova S, Wang SS, Gazova Z.
    Journal: Colloids Surf B Biointerfaces; 2018 Jun 01; 166():108-118. PubMed ID: 29550545.
    Abstract:
    Amyloid aggregates of proteins are one of the most abundant and important naturally occurring self-associated assemblies. Formation of poly/peptide amyloid aggregates is also associated with the widely spread diseases, so called amyloidosis, which include Alzheimer's disease, diabetes mellitus and lysozyme amyloidosis. These disorders are still incurable and novel therapeutical approaches are focused on using small molecules for inhibition of amyloid aggregation. We have observed effect of three structurally distinct groups of tacrine/acridone - coumarin heterodimers on hen egg white (HEW) lysozyme fibrillization in vitro. The ability of heterodimers to interfere with lysozyme amyloid aggregation was examined using Thioflavin T fluorescence assay, atomic force microscopy and docking method. The obtained data suggest that inhibitory effect of heterodimers on lysozyme fibrillization depends on their composition. We have shown that tacrine-coumarin heterodimers with alkylenediamine linker are the most effective inhibitors of lysozyme fibrillization. The inhibitory activities were quantified through IC50 values; the most potent heterodimers interfere with lysozyme aggregation in the scale of micromolar concentrations (19.2 μM-105.4 μM). The molecular docking showed that the modes of possible interactions involved in the binding are mainly hydrophobic interactions, hydrogen bonding and van der Waals interactions. Studied heterodimers had none or weak cytotoxic effect on human neuroblastoma cells. The obtained results can be helpful for the design and development of new therapeutics for amyloid-related diseases.
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