Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity
Journal
European Journal of Medicinal Chemistry
Journal Volume
158
Pages
393-404
Date Issued
2018
Author(s)
Tu, L.-H.
Tseng, N.-H.
Tsai, Y.-R.
Lin, T.-W.
Lo, Y.-W.
Charng, J.-L.
Hsu, H.-T.
Chen, Y.-S.
Chen, R.-J.
Wu, Y.-T.
Chen, C.-S.
Chen, Yun-Ru
Abstract
One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ?5.0 ? in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1–42) fibrillization. Furthermore, compound 2 effectively dissociated the Aβ(1–42) preformed fibrils. The cytotoxicity induced by Aβ(1–42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aβ transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aβ(1–40) were demonstrated by using electrospray ionization?traveling wave ion mobility?mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aβ(1–40)?2 complex. ? 2018 Elsevier Masson SAS
Other Subjects
amide; amyloid beta protein[1-40]; amyloid beta protein[1-42]; caffeic acid; caffeic acid derivative; curcumin; lonidamine; amide; amyloid beta protein; amyloid beta-protein (1-42); caffeic acid; caffeic acid derivative; peptide fragment; Article; beta sheet; Caenorhabditis elegans; controlled study; drug binding; drug design; drug potency; drug synthesis; electrospray; human; human cell; ion mobility spectrometry-mass spectrometry; neuroprotection; neurotoxicity; nonhuman; paralysis; phenotype; SH-SY5Y cell line; stoichiometry; Alzheimer disease; animal; chemistry; drug effect; metabolism; molecular model; protein multimerization; ultrastructure; Alzheimer Disease; Amides; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Caffeic Acids; Humans; Models, Molecular; Peptide Fragments; Protein Multimerization
Type
journal article