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Trehalose Conjugates of Silybin as Prodrugs for Targeting Toxic Aβ Aggregates
journal contribution
posted on 2020-08-05, 11:34 authored by Sara García-Viñuales, Rashik Ahmed, Michele F. M. Sciacca, Valeria Lanza, Maria Laura Giuffrida, Stefania Zimbone, Valeria Romanucci, Armando Zarrelli, Corrado Bongiorno, Natalia Spinella, Clelia Galati, Giovanni Di Fabio, Giuseppe Melacini, Danilo MilardiAlzheimer’s
disease (AD) is linked to the abnormal accumulation
of amyloid β peptide (Aβ) aggregates in the brain. Silybin
B, a natural compound extracted from milk thistle (Silybum
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, and (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 antiaggregation properties. Furthermore, using a
combination of biophysical techniques with different spatial resolution,
that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile
the interactions of the trehalose conjugate with both Aβ monomers
and oligomers and evidence that silybin may shield the “toxic”
surfaces formed by the N-terminal and central hydrophobic regions
of Aβ. Finally, comparative analysis with silybin A, a less
active diastereoisomer of silybin B, revealed how even subtle differences
in chemical structure may entail different 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.