9dqa
From Proteopedia
Crystal structure of bovine RPE65 in complex with EYE-002
Structural highlights
FunctionRPE65_BOVIN Plays important roles in the production of 11-cis retinal and in visual pigment regeneration. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT. The enzymatic activity is linearly dependent of the expression levels and membrane association.[1] [2] [3] Publication Abstract from PubMedThe 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. Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies.,Bassetto M, Hu Y, Li B, Chen X, Saraswat V, Damacio F, Smidak R, Palczewski K, Tochtrop GP, Kiser PD J Med Chem. 2025 Aug 28;68(16):17638-17652. doi: 10.1021/acs.jmedchem.5c01353. , Epub 2025 Aug 5. PMID:40764714[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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