Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer's disease

Inhibitions of amyloid beta (A beta) aggregation and A beta-haem peroxidase-like activity have received much attention because these two symptoms can be the primary targets of therapeutic strategies for Alzheimer's disease (AD). Recently, our group found that polyoxometalate (POM) with a Wells-Dawson structure can efficiently inhibit A beta aggregation. However, the interaction between POMs and A beta is robust, but still needs to improve A beta binding affinity. More importantly, it is unclear whether POMs can cross the blood-brain barrier and decrease A beta-haem peroxidase-like activity. Here we show that our designed series of transition metal-functionalized POM derivatives with a defined histidine-chelated binding site have much better A beta inhibition and peroxidase-like activity inhibition effects than the parent POM. More intriguingly, we show that these compounds can cross the blood-brain barrier and are metabolized after 48 h. Our work provides insights into the design, synthesis and screening of inorganic metal compounds as multifunctional therapeutic agents against AD.