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)

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)211-221
Number of pages11
JournalBioorganic Chemistry
Volume81
DOIs
Publication statusPublished - 1 Dec 2018

Fingerprint

Molecular Dynamics Simulation
Amyloid
Alzheimer Disease
Agglomeration
Monomers
Fluorescence
Peptides
Cytotoxicity
Conformations
Molecular dynamics
Molecules
Computer simulation
Therapeutics
thioflavin T

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Aβ aggregation
  • Mimetic peptides
  • Molecular docking
  • Molecular dynamics

Cite this

Gera, J., Szögi, T., Bozsó, Z., Fülöp, L., Barrera, E. E., Rodriguez, A. M., ... 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
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. / Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer. In: Bioorganic Chemistry. 2018 ; Vol. 81. pp. 211-221.
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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.",
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Gera, J, Szögi, T, Bozsó, Z, Fülöp, L, Barrera, EE, Rodriguez, AM, Méndez, L, Delpiccolo, CML, Mata, EG, Cioffi, F, Broersen, K, Paragi, G & Enriz, RD 2018, 'Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer' Bioorganic Chemistry, vol. 81, pp. 211-221. https://doi.org/10.1016/j.bioorg.2018.08.018

Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer. / 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. (Corresponding Author).

In: Bioorganic Chemistry, Vol. 81, 01.12.2018, p. 211-221.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer

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.

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KW - Amyloid β-peptide

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