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Small-Molecule Drug Repurposing for Counteracting Phototoxic A2E Aggregation
Amelie Perron1,2, Sathi Mandal1, Thiago Negrão Chuba3
1Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
ACS Chemical Biology
|September 14, 2023
Summary
Researchers found that entacapone, an FDA-approved drug, prevents the toxic aggregation of bis-retinoid A2E (a lipofuscin component). This drug repurposing approach offers photoprotection against oxidative stress in retinal cells, potentially aiding age-related macular degeneration treatment.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- Oxidative stress is implicated in age-related macular degeneration (AMD) pathogenesis.
- The precise mechanisms of phototoxicity in AMD, particularly related to lipofuscin, are not fully understood.
- Lipofuscin bis-retinoid N-retinylidene-N-retinylethanolamine (A2E) accumulates in retinal pigment epithelial cells and is photosensitive.
Purpose of the Study:
- To identify FDA-approved drugs that inhibit the aggregation and photodegradation of A2E.
- To investigate the potential of drug repurposing for developing photoprotective agents against AMD-related phototoxicity.
- To elucidate the mechanism by which A2E aggregation contributes to cellular damage.
Main Methods:
- Drug repurposing screen using fluorescence-based assays.
- Dynamic light scattering (DLS) analysis to assess A2E aggregation.
- In vitro studies using A2E-loaded retinal pigment epithelial (RPE) cells exposed to blue light.
Main Results:
- Entacapone was identified as a potent inhibitor of A2E fluorescence and aggregation.
- Entacapone treatment reduced A2E photodegradation and provided photoprotection to RPE cells.
- Mechanistic studies indicated entacapone redirects A2E into off-pathway oligomers, preventing toxic aggregate formation.
Conclusions:
- A2E aggregation is a significant contributor to its phototoxicity.
- Entacapone demonstrates potential as a photoprotective agent by inhibiting A2E aggregation.
- This study highlights a promising drug repurposing strategy for AMD therapeutics.
