Chirality-Selected Chemical Modulation of Amyloid Aggregation.

Due to the composed α-helical/ß-strand structures, ß-amyloid peptide (Aß) is sensitive to chiral environments. The orientation and chirality of the Aß strand strongly influence its aggregation. Aß-formed fibrils have a cascade of chirality. Therefore, for selectively targeting amyloid aggregates, chirality preference can be one key issue. Inspired by the natural stereoselectivity and the ß-sheet structure, herein, we synthesized a series of d- and l-amino acid-modified polyoxometalate (POM) derivatives, including positively charged amino acids (d-His and l-His) and negatively charged (d-Glu and l-Glu) and hydrophobic amino acids (d-Leu, l-Leu, d-Phe, and l-Phe), to modulate Aß aggregation. Intriguingly, Phe-modified POMs showed a stronger inhibition effect than other amino acid-modified POMs, as evidenced by multiple biophysical and spectral assays, including fluorescence, circular dichroism, NMR, molecular dynamic simulations, and isothermal titration calorimetry. More importantly, d-Phe-modified POM had an 8-fold stronger inhibition effect than l-Phe-modified POM, indicating high enantioselectivity. Furthermore, in vivo studies demonstrated that the chiral POM derivatives crossed the blood-brain barrier, extended the life span of AD transgenic Caenorhabditis elegans CL2006 strain, and had low cytotoxicity, even at a high dosage.

Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring ß-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease.

Development of sensitive detectors of Aß aggregates and effective inhibitors of Aß aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Aß fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Aß inhibitors, Aß15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Aß aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Aß-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Aß aggregates. This is the first report to integrate 3 segments, an Aß-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment.