Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer

János Gera; Titanilla Szögi; Zsolt Bozsó; Livia Fülöp; Exequiel E. Barrera; Ana M. Rodriguez; Luciana Méndez; Carina M.L. Delpiccolo; Ernesto G. Mata; Federica Cioffi; Kerensa Broersen; Gabor Paragi; Ricardo D. Enriz

doi:10.1016/j.bioorg.2018.08.018

Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β₄₂ monomer

János Gera, Titanilla Szögi, Zsolt Bozsó, Livia Fülöp, Exequiel E. Barrera, Ana M. Rodriguez, Luciana Méndez, Carina M.L. Delpiccolo, Ernesto G. Mata, Federica Cioffi, Kerensa Broersen, Gabor Paragi, Ricardo D. Enriz^* (Corresponding Author)

^*Corresponding author for this work

Nanobiophysics

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ₄₂ aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ₄₂ aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ₄₂ aggregates. The early stage interaction between compound 7 and the Aβ₄₂ 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 Aβ₄₂ 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.

Original language	English
Pages (from-to)	211-221
Number of pages	11
Journal	Bioorganic Chemistry
Volume	81
DOIs	https://doi.org/10.1016/j.bioorg.2018.08.018
Publication status	Published - 1 Dec 2018

Keywords

Alzheimer's disease
Amyloid β-peptide
Aβ aggregation
Mimetic peptides
Molecular docking
Molecular dynamics
22/4 OA procedure

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Access to Document

10.1016/j.bioorg.2018.08.018

1-s2.0-S004520681830573X-mainFinal published version, 2.35 MBLicence: Taverne

Cite this

Gera, J., Szögi, T., Bozsó, Z., Fülöp, L., Barrera, E. E., Rodriguez, A. M., Méndez, L., Delpiccolo, C. M. L., Mata, E. G., Cioffi, F., Broersen, K., Paragi, G., & Enriz, R. D. (2018). Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β₄₂ monomer. Bioorganic Chemistry, 81, 211-221. https://doi.org/10.1016/j.bioorg.2018.08.018

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title = "Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer",

abstract = "A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 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 Aβ42 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.",

keywords = "Alzheimer's disease, Amyloid β-peptide, Aβ aggregation, Mimetic peptides, Molecular docking, Molecular dynamics, 22/4 OA procedure",

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AU - Gera, János

AU - Szögi, Titanilla

AU - Bozsó, Zsolt

AU - Fülöp, Livia

AU - Barrera, Exequiel E.

AU - Rodriguez, Ana M.

AU - Méndez, Luciana

AU - Delpiccolo, Carina M.L.

AU - Mata, Ernesto G.

AU - Cioffi, Federica

AU - Broersen, Kerensa

AU - Paragi, Gabor

AU - Enriz, Ricardo D.

PY - 2018/12/1

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AB - A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 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 Aβ42 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.

KW - Alzheimer's disease

KW - Amyloid β-peptide

KW - Aβ aggregation

KW - Mimetic peptides

KW - Molecular docking

KW - Molecular dynamics

KW - 22/4 OA procedure

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