Rationally designed divalent caffeic amides inhibit amyloid-ß fibrillization, induce fibril dissociation, and ameliorate cytotoxicity.
Eur J Med Chem
; 158: 393-404, 2018 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-30227353
ABSTRACT
One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-ß (Aß) fibrils. Blocking Aß self-assembly or disassembling Aß 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 Aß fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of â¼5.0â¯Å in length, which is close to the distance of adjacent ß sheets in Aß fibrils, showed good potency to inhibit Aß(1-42) fibrillization. Furthermore, compound 2 effectively dissociated the Aß(1-42) preformed fibrils. The cytotoxicity induced by Aß(1-42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aß transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aß(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 Aß(1-40)-2 complex.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Ácidos Cafeicos
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Peptídeos beta-Amiloides
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Taiwan