Catalytic photooxygenation degrades brain Aβ in vivo.

Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst 7 that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer’s disease–related undruggable protein, amyloid-β protein (Aβ). Key was the identification of a compact but orange color visible light–activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aβ. Chemical catalyst–promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.