Designed Glycopeptidomimetics Disrupt Protein–Protein Interactions Mediating Amyloid β‑Peptide Aggregation and Restore Neuroblastoma Cell Viability

How anti-Alzheimer’s drug
candidates that reduce amyloid
1–42 peptide fibrillization interact with the most neurotoxic
species is far from being understood. We report herein the capacity
of sugar-based peptidomimetics to inhibit both Aβ1–42 early oligomerization and fibrillization. A wide range of bio- and
physicochemical techniques, such as a new capillary electrophoresis
method, nuclear magnetic resonance, and surface plasmon resonance,
were used to identify how these new molecules can delay the aggregation
of Aβ1–42. We demonstrate that these molecules
interact with soluble oligomers in order to maintain the presence
of nontoxic monomers and to prevent fibrillization. These compounds
totally suppress the toxicity of Aβ1–42 toward
SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations.
Furthermore, demonstration that the best molecule combines hydrophobic
moieties, hydrogen bond donors and acceptors, ammonium groups, and
a hydrophilic β-sheet breaker element provides valuable insight
for the future structure-based design of inhibitors of Aβ1–42 aggregation.