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

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

3D GRID-based pharmacophore and Metadynamics approaches for the rational design of N-Methyl β-sheet breaker peptides as inhibitors of the Alzheimer's Aβ-amyloid fibrillogenesis

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the loss of the cognitive functions and dementia. Several scientific evidences report that a central role in the pathogenesis of AD is played by the brain deposition of insoluble aggregates of β-amyloid protein (Aβ) proteins, thus causing neuronal cell death [1]. For this reason, one of the promising approach is to inhibit the aggregation of Aβ peptides. Because Aβ is self-assembling, one possible strategy to prevent this process is to use short peptide fragments homologous to the full-length wild-type Aβ protein. From this consideration, several short synthetic peptides were designed as beta-sheet breakers (BSB) [2]. In particular, the pentapetide Ac-LPFFD-NH2 (iAβ5p) exhibited a certain capability to inhibit Aβ fibrillogenesis [3]. iAβ5p analogs [4] were, then, designed by introducing N-Methylation at the amide bond nitrogen were also promising BSB. Here, we describe the methodological approach, which combines 3D GRID-based pharmacophore peptide screening with Well-Tempered Metadynamics simulations aimed to the discovery of novel N-Methylated BSB. This approach led us to identify two promising, cell permeable, N-Methylated peptides that were further evaluated for their BSB properties showing a significant improvement of the fibrillogenesis inhibition with respect to the lead iAβ5p

Introduction to Scheduling in Industry 4.0 and Cloud Manufacturing Systems

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Proceedings of the EUMETRISPEC workshop held at Wolfenbüttel castle and PTB Braunschweig, Nov. 15-16, 2012 (= PTB-Bericht Chemische Physik CP-8, ISSN 1614-953X)

This PTB report comprises all oral presentations and posters presented at the Nov. 2012 workshop on "Spectral reference line data for atmospheric monitoring" held at Wolfenbüttel castle and PTB Braunschweig. The workshop was organized by the EUMETRISPEC project which is part of the European Metrology Research Programme (EMRP). The main aim was to present and discuss the stakeholders\u27 views and needs. The stakeholders are from metrological organisations as well as from ground- and satellite-based monitoring networks and from quantum chemical modelling groups - in total 49 scientists representing 31 institutions from 12 nations. During the workshop, nine invited 45min-talks were given, covering spectroscopic and metrological key topics, accompanied by six additional presentations on EUMETRISPEC and the EMRP. The PTB report includes the authorized powerpoint presentations, as well as all 21 posters from 91 authors presented during the workshop.PTB-Bericht Chemische Physik CP-8. ISSN 1614-953X. ISBN 978-3-95606-034-2.collection of articles based on oral presentation at the EUMETRISPEC workshop held at Wolfenbüttel castle and PTB Praunschweig, Nov. 15-16, 201