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Switchable photooxygenation catalysts that sense higher-order amyloid structures

Nature Chemistry volume 8, pages 974–982 (2016)Cite this article

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Abstract

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, β2-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.

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Figure 1: TaSCAc approach.
Figure 2: Molecular design of cross-β-sheet-sensing photooxygenation catalysts 2 and 3.
Figure 3: Oxygenation of Aβ1–42 using a cross-β-sheet-sensing photocatalyst.
Figure 4: The rotational mobility of the axial bond between the donor and acceptor moieties of 2 as the on–off switch of the oxygenation activity.
Figure 5: Aggregation potency and cytotoxicity of oxygenated Aβ1–42.
Figure 6: Selective oxygenation of pathogenic species.

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Acknowledgements

This work was supported in part by ERATO from JST. We thank T. Katada and K. Kontani, I. Shimada and M. Kato (The University of Tokyo) for access to the ultracentrifuge, CD spectroscopy and AFM, respectively. We are grateful to Y. Goto and T. Ikenoue (Osaka University) for providing advice on the aggregation experiments of α-synuclein. We are grateful to T. Tomita, Y. Hori, K. Hanaoka and T. Komatsu (The University of Tokyo) for fruitful discussions.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

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

  2. ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Atsuhiko Taniguchi, Youhei Sohma & Motomu Kanai

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  1. Atsuhiko Taniguchi
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Contributions

A.T., Y.So. and M.K. conceived and designed the research. A.T. performed all the experiments and Y.Sh. synthesized catalyst 3. A.T., K.O., Y.So. and M.K. analysed the data. A.T., Y.So. and M.K. co-wrote the paper. All the authors discussed the results and commented on the manuscript.

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Correspondence to Youhei Sohma or Motomu Kanai.

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The authors declare no competing financial interests.

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Taniguchi, A., Shimizu, Y., Oisaki, K. et al. Switchable photooxygenation catalysts that sense higher-order amyloid structures. Nature Chem 8, 974–982 (2016). https://doi.org/10.1038/nchem.2550

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