Abstract
All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.
Footnotes
- Received October 28, 2014.
- Accepted December 23, 2014.
↵1 Current affiliation: Department of Neurology, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
This work was supported by the National Institutes of Health [Grants R01-EY009339 and R24-EY021126 to K.P. and R01-EY023948 to M.G.] and the Foundation Fighting Blindness [K.P.]. K.P. is John H. Hord Professor of Pharmacology.
K.P. and M.G. are inventors of U.S. Patent No. 8722669, “Compounds and Methods of Treating Ocular Disorders,” and U.S. Patent No. 20080275134, “Methods for Treatment of Retinal Degenerative Disease,” issued to Case Western Reserve University (CWRU), whose values may be affected by this publication. CWRU may license this technology for commercial development. K.P. is a member of the scientific board of Vision Medicine, Inc., involved in developing visual cycle modulators, and their values may be affected by this publication.
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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