Enantioselective modulation of amyloid burden and memory deficits by chiral polyoxometalates for Alzheimer's disease treatment

Preventing the formation of & beta;-amyloid peptide (A & beta;) aggregates is a promising strategy for Alzheimer's disease (AD) treatment. Given the critical influence of chirality on A & beta; aggregation, incorporation of enantioselective recognition into the design of A & beta; inhibitors is one key issue for AD therapeutics. Herein, we prepared a couple of inherent enantiomerically pure polyoxometalates (POMs) as novel chiral A & beta; inhibitors. Thanks to their chiral nature and similar size to a typical & alpha;-helix peptide, the chiral POM enantiomers exhibited different binding behavior with A & beta;40, leading to a noticeable enantioselective inhibitory effect on A & beta; aggregation. In contrast to its enantiomer l-POM, d-POM displayed a higher A & beta;40-binding affinity and greater brain biodistribution. Together with its ROS-scavenging capacity, d-POM could significantly reduce A & beta; accumulation and showed better rescue of memory deficits in AD mice. This work provides guidance for the nanoscale engineering of chiral drugs for AD therapy with similar properties.

Automated summary

Preventing Aβ aggregation is a promising strategy for Alzheimer's disease treatment. In this study, chiral polyoxometalates (POMs) were designed as novel chiral Aβ inhibitors. The chiral POM enantiomers exhibited different binding behavior with Aβ40, leading to enantioselective inhibitory effects on Aβ aggregation. The d-POM enantiomer showed higher Aβ40-binding affinity, greater brain biodistribution, and better rescue of memory deficits in AD mice.