Synthesis, biological evaluation and metadynamics simulations of novel N-methyl β-sheet breaker peptides as inhibitors of Alzheimer's β-amyloid fibrillogenesis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00585745" target="_blank" >RIV/61388963:_____/24:00585745 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1039/D4MD00057A" target="_blank" >https://doi.org/10.1039/D4MD00057A</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d4md00057a" target="_blank" >10.1039/d4md00057a</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis, biological evaluation and metadynamics simulations of novel N-methyl β-sheet breaker peptides as inhibitors of Alzheimer's β-amyloid fibrillogenesis

Popis výsledku v původním jazyce

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of β-amyloid proteins in the brain. Because Aβ is self-assembling, one possible design strategy is to inhibit the aggregation of Aβ peptides using short peptide fragments homologous to the full-length wild-type Aβ protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called β-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

Název v anglickém jazyce

Synthesis, biological evaluation and metadynamics simulations of novel N-methyl β-sheet breaker peptides as inhibitors of Alzheimer's β-amyloid fibrillogenesis

Popis výsledku anglicky

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of β-amyloid proteins in the brain. Because Aβ is self-assembling, one possible design strategy is to inhibit the aggregation of Aβ peptides using short peptide fragments homologous to the full-length wild-type Aβ protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called β-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

RSC Medicinal Chemistry

ISSN

2632-8682

e-ISSN

2632-8682

Svazek periodika

15

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

2286-2299

Kód UT WoS článku

001207382300001

EID výsledku v databázi Scopus

2-s2.0-85191322311