Small-Molecule Drug Repurposing for Counteracting Phototoxic A2E Aggregation
- Amelie Perron*
Amelie Perron*Email: [email protected]Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanInstitute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, JapanMore by Amelie Perron
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- Sathi Mandal
Sathi MandalInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Sathi Mandal
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- Thiago Negrão Chuba
Thiago Negrão ChubaInstitute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Kyoto 606-850, JapanMore by Thiago Negrão Chuba
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- Di Mao
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- Vaibhav Pal Singh
Vaibhav Pal SinghInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Vaibhav Pal Singh
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- Naotaka Noda
Naotaka NodaInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Naotaka Noda
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- Russell Tan
Russell TanInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Russell Tan
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- Hue Thi Vu
Hue Thi VuInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Hue Thi Vu
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- Masahiro Abo
Masahiro AboInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanMore by Masahiro Abo
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- Motonari Uesugi*
Motonari Uesugi*Email: [email protected]Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, JapanInstitute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, JapanMore by Motonari Uesugi
Abstract
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.
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