Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation

Area of Science:

• Biochemistry
• Neuroscience
• Medicinal Chemistry

Background:

• Alzheimer's disease (AD) pathogenesis involves amyloid β-peptide (Aβ) oligomerization and fibril formation.
• Developing effective inhibitors of Aβ aggregation is crucial for AD therapeutic strategies.

Purpose of the Study:

• To design and synthesize novel, water-soluble peptidomimetics targeting Aβ aggregation.
• To investigate the efficacy of these compounds in inhibiting amyloid fibril formation.

Main Methods:

• Synthesis of D-glucopyranosyl scaffold-based peptidomimetics with hydrophobic dipeptides.
• Thioflavin-T fluorescence assays to monitor Aβ aggregation kinetics.
• Electron microscopy to visualize amyloid fibril formation.
• NMR saturation transfer difference experiments to study molecular interactions.

Main Results:

• Peptidomimetics significantly slowed Aβ amyloid fibril formation kinetics, even at a low 0.1:1 ratio.
• Electron microscopy confirmed a reduction in typical amyloid fibrils.
• NMR studies indicated hydrophobic interactions between peptidomimetics and aggregated Aβ species.
• The inhibition was sequence-specific, with no effect on IAPP aggregation.

Conclusions:

• Novel peptidomimetics effectively inhibit Aβ aggregation through a dual hydrophobic targeting and hydrophilic sugar strategy.
• These compounds demonstrate potential as therapeutic agents for Alzheimer's disease.
• The sequence-specific inhibition highlights the targeted nature of the developed molecules.