Photo-inhibition of Aβ fibrillation mediated by a newly designed fluorinated oxadiazole

Mangione, Maria Rosalia; Piccionello, Antonio Palumbo; Mariño, Claudia; Ortore, María Grazia; Picone, Pasquale; Vilasi, Silvia; Carlo, Marta Di; Buscemi, Silvestre; Bulone, Donatella; Biagio, Pier Luigi San

doi:10.1039/c4ra13556c

Cited by 32 publications

(32 citation statements)

References 65 publications

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“…Due to the moderately low sample concentration, to the high aggregation number of amyloid fibrils that determines a low number density of scattering particles in solution, to the lowest available Q value and to the absence of interaction peaks in our SAXS curves, the interactions between fibrils have been neglected. Hence the effective structure factor S (Q) [52] has been considered equal to unity, in agreement with previous similar experimental conditions [53,54,55]. The form factor of cylinders [56] with uniform electron density ρ e , average radius R c and length L we used to represent amyloid fibrils is:…”

Section: Saxssupporting

confidence: 48%

Pressure effects on α-synuclein amyloid fibrils: An experimental investigation on their dissociation and reversible nature

Piccirilli

Plotegher

Spinozzi

et al. 2017

Archives of Biochemistry and Biophysics

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Abstractα-synuclein amyloid fibrils are found in surviving neurons of Parkinson's disease affected patients, but the role they play in the disease development is still under debate. A growing number of evidences point to soluble oligomers as the major cytotoxic species, while insoluble fibrillar aggregates could even play a protection role. In this work, we investigate α-synuclein fibrils dissociation induced at high pressure by means of Small Angle X-ray Scattering and Fourier Transform Infrared Spectroscopy. Fibrils were produced from wild type α-synuclein and two mutants associated with Parkinson's disease, A30P and A53T. Our results enlighten the different reversible nature of α-synuclein fibrils fragmentation at high pressure and suggest water excluded volumes presence in the fibrils core. Wild type and A30P species stabilized at high pressure are highly amyloidogenic and quickly re-associate into fibrils upon decompression, while A53T species shows a partial reversibility of the process likely due to the presence of an intermediate oligomeric state stabilized at high pressure. The amyloid fibrils dissociation process is here suggested to be associated to a negative activation volume, supporting the notion that α-synuclein fibrils are in a high-volume and high-compressibility state and hinting at the presence of a hydration-mediated activated state from which dissociation occurs.

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Section: Saxssupporting

confidence: 48%

Pressure effects on α-synuclein amyloid fibrils: An experimental investigation on their dissociation and reversible nature

Piccirilli

Plotegher

Spinozzi

et al. 2017

Archives of Biochemistry and Biophysics

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“…P 1 (Q), P 7 (Q), and P 14 (Q) are accordingly the form factors corresponding to GroEL/Hsp60 monomers, heptamers and tetradecamers. P U (Q) is the Pedersen-Schurtenberger worm-like chain form factor [28] multiplied by a two-electron density level cross section for the protein chain as used in previous studies [29,30] and N agg is the aggregation number of monomers arranged in the worm-like species. Protein form factors corresponding to tetradecamers, heptamers and monomers have been obtained from the PDB entries by taking into account water molecule positions at the hydration shell of each oligomer, according to the SASMOL approach [31], and the relative mass density of proteins' first hydration shell ρ 1 /ρ 0 has been considered a fitting parameter.…”

Section: Resultsmentioning

confidence: 99%

Stability and disassembly properties of human naïve Hsp60 and bacterial GroEL chaperonins

Ricci

Ortore

Vilasi

et al. 2016

Biophysical Chemistry

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“…These compounds are two different oxadiazole regio-isomers, two heterocyclic nuclei widely studied for AD treatment. 33,41 Oxazole derivatives were not considered, due to unproductive preliminary synthetic attempts. In particular, following Scheme 1, the 1,2,4-oxadiazole derivative 4, was obtained by adopting the conventional amidoxime route, 42 starting from the ester 2 and amidoxime 3.…”

Section: Resultsmentioning

confidence: 99%

“…The cytotoxicity of the compounds and their effect on Ab 1-40 aggregation in vitro, were studied on the LAN5 neuroblastoma cell line through an MTT assay, by adapting a previously reported procedure. 33 Cells were treated with both compounds 4 and 7 at 1 and 5 mM doses, respectively. Taking into account the cytotoxicity potential of Ab 1-40 in aggregated species, LAN5 cells were treated using aliquots taken during Ab 1-40 aggregation kinetics at 50 mM in the absence and presence of the oxadiazoles 4 and 7, each one at 5 mM.…”

Section: Biological Evaluationmentioning

confidence: 99%

Curcumin-like compounds designed to modify amyloid beta peptide aggregation patterns

et al. 2017

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Curcumin is a natural polyphenol able to bind the amyloid beta peptide, which is related to Alzheimer’s\ud disease, and modify its self-assembly pathway. This paper focuses on a multi-disciplinary study that starts\ud from the design of curcumin-like compounds with the key chemical features required for inhibiting\ud amyloid beta aggregation, and reports the effects of these compounds on the in vitro aggregation of\ud amyloid beta peptides. Chemoinformatic screening was performed through the calculation of molecular\ud descriptors that were able to highlight the drug-like profile, followed by docking studies with an amyloid\ud beta peptide fibril. The computational design underlined two different scaffolds that were easily\ud synthesized in good yields. In vitro experiments, ranging from fluorescence spectroscopy and confocal\ud microscopy up to small angle X-ray scattering, provided evidence that the synthesized compounds are\ud able to modify the aggregation pattern of amyloid beta peptides both in the secondary structures, and in\ud terms of the overall structure dimensions. The cytotoxic potential of the synthesized compounds was\ud finally tested in vitro with a model neuronal cell line (LAN5). The overall view of this study suggests new\ud concepts and potential difficulties in the design of novel drugs against diverse amyloidoses, including\ud Alzheimer’s disease

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Photo-inhibition of Aβ fibrillation mediated by a newly designed fluorinated oxadiazole

Abstract: The interaction of oxadiazole3photo-stimulated with Aβ1–40induces a structural modification responsible for fibrillogenesis inhibition.

Cited by 32 publications

References 65 publications

Pressure effects on α-synuclein amyloid fibrils: An experimental investigation on their dissociation and reversible nature

Pressure effects on α-synuclein amyloid fibrils: An experimental investigation on their dissociation and reversible nature

Stability and disassembly properties of human naïve Hsp60 and bacterial GroEL chaperonins

Curcumin-like compounds designed to modify amyloid beta peptide aggregation patterns

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