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Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β 42 monomer

A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicit...

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Bibliographic Details
Published in:Bioorganic chemistry 2018-12, Vol.81, p.211
Main Authors: Gera, János, Szögi, Titanilla, Bozsó, Zsolt, Fülöp, Livia, Barrera, Exequiel E, Rodriguez, Ana M, Méndez, Luciana, Delpiccolo, Carina M L, Mata, Ernesto G, Cioffi, Federica, Broersen, Kerensa, Paragi, Gabor, Enriz, Ricardo D
Format: Article
Language:English
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Summary:A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ aggregates. The early stage interaction between compound 7 and the Aβ monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early "on-pathway" events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer's disease.
ISSN:1090-2120
DOI:10.1016/j.bioorg.2018.08.018