5ul5
Crystal structure of RPE65 in complex with MB-004 and palmitate
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 PubMedModulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase (RPE65), the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Certain of these agents that contain primary amine groups also can also reversibly form retinaldehyde-Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehyde-sequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with high affinity for the RPE65 active site. These agents distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound (MB-007), these agents conferred protection against retinal phototoxicity suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance. Rational tuning of visual cycle modulator pharmacodynamics.,Kiser PD, Zhang J, Badiee M, Kinoshita J, Peachey NS, Tochtrop GP, Palczewski K J Pharmacol Exp Ther. 2017 May 5. pii: jpet.117.240721. doi:, 10.1124/jpet.117.240721. PMID:28476927[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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