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Light-Activated RPE65 Inhibitors Enable On-Demand Visual Cycle Control
Marco Bassetto1,2,3, Bowen Li4, Xiuyuan Chen4
1Department of Physiology and Biophysics, University of California, Irvine, Irvine, California 92697, United States.
Abstract:
Light initiates visual perception, but it also exacerbates a subset of blinding diseases in which visual (retinoid) cycle metabolic intermediates contribute to pathophysiology. Small molecule visual cycle modulators (VCMs) have demonstrated efficacy in preclinical models, but have been limited clinically by chronic, indiscriminate visual cycle suppression leading to side effects including night blindness in human subjects. Here, we demonstrate VCMs that are activated via a Z→E photoisomerization of an azobenzene-containing VCM by visible light within the eye. One such VCM photoswitch, (Z)-9, is a weak inhibitor of the visual cycle isomerohydrolase, RPE65, that affords potent, rapid, and on-demand inhibition when photoisomerized to the E-configuration by visible light. (E)-9 protects the retina from visual cycle toxicity and, after oral administration, shows a shorter pharmacodynamic duration than emixustat as measured by electroretinography. These results establish posterior-segment photopharmacology and outline a blueprint for light-activated therapies that mitigate daytime toxicity while sparing night vision.
Insights
New light-activated therapies use photoswitchable visual cycle modulators (VCMs) to treat blinding diseases. This approach allows on-demand drug delivery, reducing side effects like night blindness and protecting retinal health.
Area of Science:
- Ophthalmology
- Pharmacology
- Biochemistry
Background:
- Light is crucial for vision but can worsen blinding diseases linked to the visual (retinoid) cycle.
- Current visual cycle modulators (VCMs) cause side effects like night blindness due to chronic suppression.
Purpose of the Study:
- To develop novel VCMs activated by visible light through Z→E photoisomerization.
- To create light-inducible VCMs for targeted, on-demand inhibition of the visual cycle.
Main Methods:
- Synthesized azobenzene-containing VCMs, including (Z)-9.
- Investigated the photoisomerization of (Z)-9 to its active E-configuration using visible light.
- Assessed the efficacy of (E)-9 in protecting the retina from toxicity and its pharmacodynamic duration compared to emixustat via electroretinography.
Main Results:
- (Z)-9, a weak RPE65 inhibitor, becomes potent upon light-activated Z→E isomerization.
- (E)-9 demonstrated retinal protection against visual cycle toxicity.
- Oral administration of (E)-9 exhibited a shorter duration of action than emixustat.
Conclusions:
- Established posterior-segment photopharmacology using light-activated VCMs.
- Developed a blueprint for therapies mitigating daytime toxicity while preserving night vision.
- Demonstrated the potential of light-activated VCMs for safer, more effective treatment of blinding retinopathies.
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