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Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry

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Inhibition of Aβ Amyloid Growth and Toxicity by Silybins : The Crucial Role of Stereochemistry. / Sciacca, Michele F.M.; Romanucci, Valeria; Zarrelli, Armando; Monaco, Irene; Lolicato, Fabio; Spinella, Natalia; Galati, Clelia; Grasso, Giuseppe; D'Urso, Luisa; Romeo, Margherita; Diomede, Luisa; Salmona, Mario; Bongiorno, Corrado; Di Fabio, Giovanni; La Rosa, Carmelo; Milardi, Danilo.

In: ACS Chemical Neuroscience, Vol. 8, No. 8, 16.08.2017, p. 1767-1778.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Sciacca, MFM, Romanucci, V, Zarrelli, A, Monaco, I, Lolicato, F, Spinella, N, Galati, C, Grasso, G, D'Urso, L, Romeo, M, Diomede, L, Salmona, M, Bongiorno, C, Di Fabio, G, La Rosa, C & Milardi, D 2017, 'Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry', ACS Chemical Neuroscience, vol. 8, no. 8, pp. 1767-1778. https://doi.org/10.1021/acschemneuro.7b00110

APA

Sciacca, M. F. M., Romanucci, V., Zarrelli, A., Monaco, I., Lolicato, F., Spinella, N., ... Milardi, D. (2017). Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry. ACS Chemical Neuroscience, 8(8), 1767-1778. https://doi.org/10.1021/acschemneuro.7b00110

Vancouver

Sciacca MFM, Romanucci V, Zarrelli A, Monaco I, Lolicato F, Spinella N et al. Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry. ACS Chemical Neuroscience. 2017 Aug 16;8(8):1767-1778. https://doi.org/10.1021/acschemneuro.7b00110

Author

Sciacca, Michele F.M. ; Romanucci, Valeria ; Zarrelli, Armando ; Monaco, Irene ; Lolicato, Fabio ; Spinella, Natalia ; Galati, Clelia ; Grasso, Giuseppe ; D'Urso, Luisa ; Romeo, Margherita ; Diomede, Luisa ; Salmona, Mario ; Bongiorno, Corrado ; Di Fabio, Giovanni ; La Rosa, Carmelo ; Milardi, Danilo. / Inhibition of Aβ Amyloid Growth and Toxicity by Silybins : The Crucial Role of Stereochemistry. In: ACS Chemical Neuroscience. 2017 ; Vol. 8, No. 8. pp. 1767-1778.

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@article{ad5e0799268d40aaa7ab07866320396d,
title = "Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry",
abstract = "The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the {"}amyloid hypothesis{"}, many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.",
keywords = "Alzheimer's disease, Chiral drugs, natural compounds, neurodegeneration, neuroprotection",
author = "Sciacca, {Michele F.M.} and Valeria Romanucci and Armando Zarrelli and Irene Monaco and Fabio Lolicato and Natalia Spinella and Clelia Galati and Giuseppe Grasso and Luisa D'Urso and Margherita Romeo and Luisa Diomede and Mario Salmona and Corrado Bongiorno and {Di Fabio}, Giovanni and {La Rosa}, Carmelo and Danilo Milardi",
year = "2017",
month = "8",
day = "16",
doi = "10.1021/acschemneuro.7b00110",
language = "English",
volume = "8",
pages = "1767--1778",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "8",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Inhibition of Aβ Amyloid Growth and Toxicity by Silybins

T2 - The Crucial Role of Stereochemistry

AU - Sciacca, Michele F.M.

AU - Romanucci, Valeria

AU - Zarrelli, Armando

AU - Monaco, Irene

AU - Lolicato, Fabio

AU - Spinella, Natalia

AU - Galati, Clelia

AU - Grasso, Giuseppe

AU - D'Urso, Luisa

AU - Romeo, Margherita

AU - Diomede, Luisa

AU - Salmona, Mario

AU - Bongiorno, Corrado

AU - Di Fabio, Giovanni

AU - La Rosa, Carmelo

AU - Milardi, Danilo

PY - 2017/8/16

Y1 - 2017/8/16

N2 - The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.

AB - The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.

KW - Alzheimer's disease

KW - Chiral drugs

KW - natural compounds

KW - neurodegeneration

KW - neuroprotection

U2 - 10.1021/acschemneuro.7b00110

DO - 10.1021/acschemneuro.7b00110

M3 - Article

VL - 8

SP - 1767

EP - 1778

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 8

ER -