Trehalose conjugates of silybin as prodrugs for targeting toxic Aβ aggregates.

Alzheimer's Disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) in the brain. Silybin B, a natural compound extracted from milk thistle (Silibum marianum), has been shown to significantly inhibit Aβ aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility; (b) instability in blood serum; (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its anti-aggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolutions, i.e. TEM, ThT fluorescence, CD, and NMR spectroscopy, we profiled the interactions of the trehalose conjugate with both Aβ monomers and oligomers. Finally, the comparative analysis with silybin A, a less active diastereomer of silybin B, revealed how even subtle differences in chemical structure may entail significantly divergent effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.