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

Abstract

Preventing the formation of β-amyloid peptide (Aβ) aggregates is a promising strategy for Alzheimer's disease (AD) treatment. Given the critical influence of chirality on Aβ aggregation, incorporation of enantioselective recognition into the design of Aβ inhibitors is one key issue for AD therapeutics. Herein, we prepared a couple of inherent enantiomerically pure polyoxometalates (POMs) as novel chiral Aβ inhibitors. Thanks to their chiral nature and similar size to a typical α-helix peptide, the chiral POM enantiomers exhibited different binding behavior with Aβ40, leading to a noticeable enantioselective inhibitory effect on Aβ aggregation. In contrast to its enantiomer L-POM, D-POM displayed a higher Aβ40-binding affinity and greater brain biodistribution. Together with its ROS-scavenging capacity, D-POM could significantly reduce Aβ 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.