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

Moraca, Federica; Vespoli, Ilaria; Mastroianni, Domenico; Piscopo, Vincenzo; Gaglione, Rosa; Arciello, Angela; De Nisco, Mauro; Pacifico, Severina; Catalanotti, Bruno; Pedatella, Silvana

doi:10.1039/d4md00057a

RSC Med. Chem.

2024

DOI: 10.1039/d4md00057a

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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

Federica Moraca,

Ilaria Vespoli,

Domenico Mastroianni

et al.

Abstract: Several scientific evidences report that a central role in the pathogenesis of Alzheimer’s Disease is played by the brain deposition of insoluble aggregates of β-amyloid proteins. Because Aβ is self-assembling,...

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Cited by 3 publications

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Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β‐amyloid Peptide Aggregation

Lemos,

Pérez‐Badell,

De Nisco

et al. 2024

ChemPlusChem

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The aggregation of β‐amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel–Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP‐D3(BJ)/6‐311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ‐peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells.

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Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β‐amyloid Peptide Aggregation

Lemos,

Pérez‐Badell,

De Nisco

et al. 2024

ChemPlusChem

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Unveiling molecular mechanism underlying inhibition of human islet amyloid polypeptide fibrillation by benzene carboxylic acid-peptide conjugate

Mehta,

Goyal

2024

Journal of Molecular Liquids

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Inhibition of α-Synuclein Misfolding into β-Sheet Domains on Medium-Sized Gold Nanoclusters: Evidence from Enhanced Sampling MD Simulations

Gong,

Gao,

Sun

et al. 2024

ACS Macro Lett.

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Targeting Parkinson's disease (PD) related protein, α-synuclein (αS), via gold nanoclusters (AuNCs) has received considerable attention in PD treatments, but its molecular basis on the initial interactions between αS and AuNCs remains elusive due to the absence of a unique secondary structure of αS chains. Here, at the single-cluster level, we incorporate well-tempered metadynamics simulations to explore the structural and thermodynamic characteristics of the full length αS adsorbed on different-sized AuNCs (Au n , n = 25, 36, 44, 68, 102) with modeled thiolated ligands (Au n @Lig). The conformational landscapes of αS indicate that uncharged Au n @SCH 2 OH chaperones the native intrinsically disordered conformations of αS, while negatively and positively charged AuNCs greatly increase the likelihood of forming intramolecular β-sheet domains, which are necessary for αS fibrillation and are a hallmark of PD. The binding details further demonstrate the significant inhibitory effect of the medium-sized Au 36 @SCH 2 OH on αS misfolding into β-sheet domains. This provides a valuable guideline for customizing AuNCs to precisely manipulate protein folding and misfolding behaviors, with potential implications for disease treatments.

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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

Abstract: Several scientific evidences report that a central role in the pathogenesis of Alzheimer’s Disease is played by the brain deposition of insoluble aggregates of β-amyloid proteins. Because Aβ is self-assembling,...

Cited by 3 publications

References 81 publications

Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β‐amyloid Peptide Aggregation

Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β‐amyloid Peptide Aggregation

Unveiling molecular mechanism underlying inhibition of human islet amyloid polypeptide fibrillation by benzene carboxylic acid-peptide conjugate

Inhibition of α-Synuclein Misfolding into β-Sheet Domains on Medium-Sized Gold Nanoclusters: Evidence from Enhanced Sampling MD Simulations

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