Development of Artificial Catalysts that Selectively Photooxygenate Pathogenic Amyloid

Abstract

Aggregation of peptide/protein is intimately related to a number of human diseases. More than twenty have been identified to aggregate into fibrils containing extensive β-sheet structures, and species generated in the aggregation processes (i.e., oligomers, protofibrils, and fibrils) contribute to disease development. Amyloid-β (designated Aβ), related to Alzheimer disease (AD), is the representative example. Artificial chemical transformation of toxic, aberrant Aβ to less toxic forms at the disease site might be a new candidate for AD treatment. Thus, covalent installation of hydrophilic oxygen atoms to Aβ using aerobic oxygen and visible light as oxygen atom- and energy sources, respectively, in the presence of a catalyst (i.e., catalytic photooxygenation) was used. Selective, cell-compatible photo-oxygenation of Aβ by a flavin catalyst attached to an Aβ-binding peptide markedly decreased aggregation potency and neurotoxicity of Aβ. In addition, we designed photooxygenation catalysts that can be turned on only when binding with the higher-order structures of amyloid aggregates. This on/off switchable activity of the catalyst that senses amyloid structure enabled highly Aβ-selective oxygenation in the presence of other bioactive peptides and living cells. Moreover, we succeeded to develop next-level switchable oxygenation catalysts that can be activated by a near-infrared light. The catalyst induced photooxygenation of Aβ in the brains of living mice, leading to significant reduction of Aβ in the brain.