アミロイド病治療を目指したアミロイド選択的光酸素化

抄録

 Amyloid proteins and peptides form aggregates which lead to amyloid diseases. For example, Alzheimer's disease-related amyloid β (Aβ) forms oligomers, protofibrils, and amyloid fibrils, which exhibit neurotoxicity. Controlling the aggregation and toxicity of Aβ would be a therapeutic strategy for the treatment of Alzheimer's disease. Recently, we have investigated an artificial oxygenative modification (chemical introduction of oxygen atoms) of amyloid proteins using a photocatalyst, which attenuated the aggregation potency and toxicity of these proteins. The oxygenation of Aβ1-42 was efficiently induced using a riboflavin catalyst (1). The oxygenated Aβ was less aggregative and cytotoxic than native Aβ. The oxygenated Aβ also showed inhibitory activity against aggregation and the onset of toxicity of native Aβ. Flavin catalyst 2, bearing an Aβ-binding peptide, allowed the selective oxygenation of Aβ even in the presence of living cells, due to its Aβ-affinity. Furthermore, “On/Off” switchable photooxygenation catalysts 3 and 4, which can sense a higher-order amyloid structure (i.e., cross-β-sheet structure), were developed based on the amyloid fluorescence probe thioflavin-T. The photo-excited catalysts generated singlet oxygens to induce oxygenation when binding to the amyloid structure (“On”). In contrast, the free catalysts, without binding to the amyloid structure, produced no singlet oxygen, even if photo-excited (“Off”). This “On/Off” switchable function enabled highly Aβ-selective oxygenation. Catalyst 3 was successfully used for the selective oxygenation of other amyloid proteins and peptides. These findings suggest that amyloid-selective oxygenation could provide a versatile system in developing effective new treatments for amyloid diseases.