Journal Article

Switchable photooxygenation catalysts that sense higher-order amyloid structures

Taniguchi, Atsuhiko, Oisaki, Kounosuke, Sohma, Youhei, Shimizu, Yusuke, Kanai, Motomu

2016

Overview

Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1–42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β 2 -microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein. Selectively degrading the pathogenic, aggregated amyloid state of proteins, without affecting the functional state, is a potential therapeutic strategy for treating amyloid diseases. Now, photooxygenation catalysts that are active only when bound to the cross-β-sheet structure of the amyloid form have been developed.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 639/638/439/890 / 639/638/45/611 / 639/638/92/470/2284 / 639/638/92/612 / Aggregates / alpha-Synuclein - chemistry / alpha-Synuclein - metabolism / Alzheimer's disease / Amyloid - chemistry / Amyloid - metabolism / Amyloid beta-Peptides - chemistry / Amyloid beta-Peptides - metabolism / Analytical Chemistry / Animals / Benzothiazoles - chemistry / Benzothiazoles - metabolism / Benzothiazoles - radiation effects / Benzothiazoles - toxicity / beta 2-Microglobulin - chemistry / beta 2-Microglobulin - metabolism / Biochemistry / Catalysis / Chemistry / Chemistry/Food Science / Drug Design / Humans / Inorganic Chemistry / Insulin - chemistry / Insulin - metabolism / Islet Amyloid Polypeptide - chemistry / Islet Amyloid Polypeptide - metabolism / Ligands / Light / Models, Chemical / Oligopeptides - chemistry / Oligopeptides - metabolism / Oligopeptides - radiation effects / Oligopeptides - toxicity / Organic Chemistry / Oxidation-Reduction / Pathogens / PC12 Cells / Peptide Fragments - chemistry / Peptide Fragments - metabolism / Peptides / Physical Chemistry / Physiology / Prealbumin - chemistry / Prealbumin - metabolism / Protein Binding / Protein Multimerization / Proteins / Quantum Theory / Rats / Singlet Oxygen - chemistry / Toxicity