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

Michele F M Sciacca, Valeria Romanucci, Armando Zarrelli, Irene Monaco, Fabio Lolicato, Natalia Spinella, Clelia Galati, Giuseppe Grasso, Luisa D'Urso, Margherita Romeo, Luisa Diomede, Mario Salmona, Corrado Bongiorno, Giovanni Di Fabio, Carmelo La Rosa, Danilo Milardi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1767-1778
Number of pages12
JournalACS Chemical Neuroscience
Issue number8
Publication statusPublished - Aug 16 2017


  • Amyloid beta-Peptides
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Caenorhabditis elegans
  • Dose-Response Relationship, Drug
  • Microscopy, Atomic Force
  • Microscopy, Electron, Transmission
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Aggregation, Pathological
  • Protein Conformation
  • Silymarin
  • Journal Article


Dive into the research topics of 'Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry'. Together they form a unique fingerprint.

Cite this