A Near-Infrared-Controllable Artificial Metalloprotease Used for Degrading Amyloid-β Monomers and Aggregates

Proteolysis of amyloid-beta (A beta) is a promising approach against Alzheimer's disease. However, it is not feasible to employ natural hydrolases directly because of their cumbersome preparation and purification, poor stability, and hazardous immunogenicity. Therefore, artificial enzymes have been developed as potential alternatives to natural hydrolases. Since specific cleavage sites of A beta are usually embedded inside the beta-sheet structures that restrict access by artificial enzymes, this strongly hinders their efficiency for practical applications. Herein, we construct a NIR (near-IR) controllable artificial metalloprotease (MoS2-Co) using a molybdenum disulfide nanosheet (MoS2) and a cobalt complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Codota). Evidenced by detailed experimental and theoretical studies, the NIR-enhanced MoS2-Co can circumvent the restriction by simultaneously inhibition of beta-sheet formation and destroying beta-sheet structures of the preformed A beta aggregates in living cell. Furthermore, our designed MoS2-Co is an easy to graft A beta-target agent that prevents misdirected or undesirable hydrolysis reactions, and has been demonstrated to cross the blood brain barrier. This method can be adapted for hydrolysis of other kinds of amyloids.