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

F. Moraca, I. Vespoli, D. Mastroianni, V. Piscopo, R. Gaglione, A. Arciello, M. De Nisco, S. Pacifico, B. Catalanotti, S. Pedatella

. 2024 ; 15 (7) : 2286-2299. [pub] 20240411

Status neindexováno Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018215

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.

Citace poskytuje Crossref.org

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