TY - JOUR T1 - Expansion of First-in-class Drug Candidates that Sequester Toxic All-trans-retinal and Prevent Light-induced Retinal Degeneration JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.096560 SP - mol.114.096560 AU - Jianye Zhang AU - Zhiqian Dong AU - Sreenivasa Mundla AU - X Eric Hu AU - William Seibel AU - Ruben Papoian AU - Krzysztof Palczewski AU - Marcin Golczak Y1 - 2014/12/23 UR - http://molpharm.aspetjournals.org/content/early/2014/12/23/mol.114.096560.abstract N2 - Visual cycle inhibitors (modulators) have gained significant recognition as potential therapeutics to prevent retinal degeneration. We discovered that all-trans-retinal, a retinoid metabolite naturally produced during visual processing, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, we identified the first-in-class drug candidates that transiently sequester this metabolite. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyl transferase (LRAT) is the enzyme that initially traps vitamin A (retinol) from the circulation and photoreceptor cells to produce the esterified substrate for the second enzyme, retinoid isomerase (RPE65) which converts the all-trans-retinyl ester to an 11-cis-retinol. Thus the pharmacologically active compounds and substrates of LRAT could be selectively delivered to the eye. However, the chemical similarity of LRAT's substrate and RPE65 inhibitors could affect the isomerase and produce delayed dark adaptation, a debilitating visual problem for humans. Here we delineate certain chemical boundaries for LRAT substrate and RPE65 inhibitor specificities together with their protection against retinal degeneration in mice. ER -