9oa5
Crystal structure of bovine RPE65 in complex with an emixustat azolog
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 PubMedLight 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. Light-Activated RPE65 Inhibitors Enable On-Demand Visual Cycle Control.,Bassetto M, Li B, Chen X, Zhang J, Hu Y, Zaluski J, Brumit LM, Willis PM, Grun F, Palczewski K, Kiser PD, Tochtrop GP J Am Chem Soc. 2026 May 19. doi: 10.1021/jacs.6c02962. PMID:42156327[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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