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Small-Molecule Drug Repurposing for Counteracting Phototoxic A2E Aggregation

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    Small-Molecule Drug Repurposing for Counteracting Phototoxic A2E Aggregation
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    • Amelie Perron*
      Amelie Perron
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
      Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan
      *Email: [email protected]
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    • Sathi Mandal
      Sathi Mandal
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
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    • Thiago Negrão Chuba
      Thiago Negrão Chuba
      Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Kyoto 606-850, Japan
      More by Thiago Negrão Chuba
    • Di Mao
      Di Mao
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
      More by Di Mao
    • Vaibhav Pal Singh
      Vaibhav Pal Singh
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
      More by Vaibhav Pal Singh
    • Naotaka Noda
      Naotaka Noda
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
      More by Naotaka Noda
    • Russell Tan
      Russell Tan
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
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    • Hue Thi Vu
      Hue Thi Vu
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
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    • Masahiro Abo
      Masahiro Abo
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
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    • Motonari Uesugi*
      Motonari Uesugi
      Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
      Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan
      *Email: [email protected]
      More by Motonari Uesugi
      Orcidhttps://orcid.org/0000-0002-8515-445X
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2023, 18, 10, 2170–2175
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    https://doi.org/10.1021/acschembio.3c00339
    Published September 14, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Despite the well-established role of oxidative stress in the pathogenesis of age-related macular degeneration (AMD), the mechanism underlying phototoxicity remains unclear. Herein, we used a drug repurposing approach to isolate an FDA-approved drug that blocks the aggregation of the photoinducible major fluorophore of lipofuscin, the bis-retinoid N-retinylidene-N-retinylethanolamine (A2E). Our fluorescence-based screening combined with dynamic light scattering (DLS) analysis led to the identification of entacapone as a potent inhibitor of A2E fluorescence and aggregation. The entacapone-mediated inhibition of A2E aggregation blocks its photodegradation and offers photoprotection in A2E-loaded retinal pigment epithelial (RPE) cells exposed to blue light. In-depth mechanistic analysis suggests that entacapone prevents the conversion of toxic aggregates by redirecting A2E into off-pathway oligomers. These findings provide evidence that aggregation contributes to the phototoxicity of A2E.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.3c00339.

    • Additional experimental details, including hit compound structures, LC-MS chromatograms of A2E, 1H NMR spectra of entacapone, A2E photodegradation products, and FE-SEM imaging of A2E with or without entacapone (PDF)

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    Cited By

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    This article is cited by 1 publications.

    1. Nicoletta Marchesi, Martina Capierri, Alessia Pascale, Annalisa Barbieri. Different Therapeutic Approaches for Dry and Wet AMD. International Journal of Molecular Sciences 2024, 25 (23) , 13053. https://doi.org/10.3390/ijms252313053
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2023, 18, 10, 2170–2175
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschembio.3c00339
    Published September 14, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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