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.

Department of Chemical Sciences University of Napoli Federico 2 Via Cintia 4 1 80126 Napoli Italy

Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania Luigi Vanvitelli Viale Abramo Lincoln 5 1 81100 Caserta Italy

Department of Pharmacy University of Napoli Federico 2 Via Domenico Montesano 49 1 80131 Napoli Italy

Department of Sciences University of Basilicata Viale dell'Ateneo Lucano 1 85100 Potenza Italy

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542 2 CZ 16610 Prague Czech Republic

Istituto Nazionale di Biostrutture e Biosistemi Viale delle Medaglie d'Oro 305 1 80145 Roma Italy

Net4Science Academic Spin Off University Magna Græcia of Catanzaro Viale Europa 88100 Catanzaro Italy

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