Chirality-Selected Chemical Modulation of Amyloid Aggregation.

Area of Science:

• Biochemistry
• Materials Science
• Neuroscience

Background:

• β-amyloid peptide (Aβ) aggregation is central to Alzheimer's disease pathogenesis.
• Aβ aggregation is influenced by chiral environments and exhibits inherent chirality.
• Targeting Aβ aggregation requires strategies that consider stereoselectivity.

Purpose of the Study:

• To synthesize chiral amino acid-modified polyoxometalate (POM) derivatives.
• To investigate the effect of these POMs on Aβ aggregation.
• To evaluate the therapeutic potential of enantioselective POMs in Alzheimer's disease models.

Main Methods:

• Synthesis of d- and l-amino acid-modified POMs (His, Glu, Leu, Phe).
• Biophysical and spectral assays (fluorescence, CD, NMR, MD simulations, ITC) to assess Aβ aggregation inhibition.
• In vivo studies using AD transgenic C. elegans (CL2006 strain).

Main Results:

• Phenylalanine-modified POMs exhibited superior Aβ aggregation inhibition compared to other amino acid derivatives.
• d-Phe-modified POM showed an 8-fold greater inhibition than l-Phe-modified POM, demonstrating high enantioselectivity.
• In vivo studies confirmed blood-brain barrier penetration, lifespan extension in AD models, and low cytotoxicity.

Conclusions:

• Chiral POMs, especially d-Phe-POM, are potent and enantioselective inhibitors of Aβ aggregation.
• These findings highlight the potential of chiral POMs as therapeutic agents for Alzheimer's disease.
• The study underscores the importance of chirality in designing effective Aβ aggregation inhibitors.