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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 not-indexed Language English Country England, Great Britain

Document type Journal Article

Persistent link   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.

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$a Vespoli, Ilaria $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542/2 CZ-16610 Prague Czech Republic
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$a Mastroianni, Domenico $u Department of Chemical Sciences, University of Napoli Federico II Via Cintia 4 I-80126 Napoli Italy
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$a Piscopo, Vincenzo $u Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli" Viale Abramo Lincoln 5 I-81100 Caserta Italy
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$a Gaglione, Rosa $u Department of Chemical Sciences, University of Napoli Federico II Via Cintia 4 I-80126 Napoli Italy $u Istituto Nazionale di Biostrutture e Biosistemi (INBB) Viale delle Medaglie d'Oro 305 I-80145 Roma Italy
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$a Arciello, Angela $u Department of Chemical Sciences, University of Napoli Federico II Via Cintia 4 I-80126 Napoli Italy $u Istituto Nazionale di Biostrutture e Biosistemi (INBB) Viale delle Medaglie d'Oro 305 I-80145 Roma Italy
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$a De Nisco, Mauro $u Department of Sciences, University of Basilicata Viale dell'Ateneo Lucano I-85100 Potenza Italy mauro.denisco@unibas.it $1 https://orcid.org/0009000194103072
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$a Pacifico, Severina $u Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli" Viale Abramo Lincoln 5 I-81100 Caserta Italy
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