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

Inhibitions of amyloid β (Aβ) aggregation and Aβ-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 Aβ aggregation. However, the interaction between POMs and Aβ is robust, but still needs to improve Aβ binding affinity. More importantly, it is unclear whether POMs can cross the blood–brain barrier and decrease Aβ-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 Aβ 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.