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Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies
Marco Bassetto1,2,3, Yulun Hu4, Bowen Li4
1Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California 92697, United States.
Abstract:
The visual cycle is a metabolic pathway essential for visual function. The bisretinoid byproducts of this pathway can induce retinal toxicity, as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits bisretinoid production, is a visual cycle modulator (VCM) that targets RPE65. However, it causes visual impairment due to its unfavorable duration of action. Here, we report ester-containing analogs of emixustat that are susceptible to hydrolytic clearance and function as short-acting VCMs. We show that the esterase-mediated metabolism of these compounds can be tuned while maintaining high-affinity RPE65 targeting. Compounds 6 (EYE-002) and 7 (EYE-003) containing diethyl acetate and valproate esters, respectively, allowed faster recovery of visual cycle function compared to emixustat. These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat.
Insights
New visual cycle modulators offer faster recovery and fewer side effects. These short-acting compounds target RPE65, protecting against retinal degeneration in Stargardt disease and related conditions.
Area of Science:
- Biochemistry
- Ophthalmology
- Pharmacology
Background:
- The visual cycle is crucial for vision, but its byproducts can cause retinal toxicity, exemplified by Stargardt disease type 1 (STGD1).
- Emixustat, a visual cycle modulator (VCM) targeting RPE65, inhibits toxic bisretinoid production but has a prolonged duration of action causing visual impairment.
Purpose of the Study:
- To develop novel, short-acting VCMs with improved safety profiles.
- To investigate ester-containing emixustat analogs for tunable hydrolytic clearance and faster visual cycle recovery.
Main Methods:
- Synthesis of ester-containing emixustat analogs.
- Assessment of RPE65 targeting affinity and esterase-mediated metabolism.
- Evaluation of visual cycle recovery kinetics in vitro and in vivo.
- Testing efficacy in mouse models of photic retinopathy and STGD1.
Main Results:
- Ester analogs demonstrated tunable metabolism and maintained high-affinity RPE65 targeting.
- Compounds 6 (EYE-002) and 7 (EYE-003) showed faster visual cycle function recovery than emixustat.
- These novel VCMs provided protection against retinal degeneration in disease models.
Conclusions:
- Short-acting VCMs based on emixustat analogs offer a promising therapeutic strategy for retinal diseases.
- Tunable esterase-mediated clearance allows for optimized duration of action, potentially reducing visual side effects.
- These findings highlight the therapeutic potential of controlled visual cycle modulation for treating STGD1 and related retinopathies.
