Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration
| Autor: | Zhiqian Dong, William L. Seibel, Ruben Papoian, Sreenivasa R. Mundla, X. Eric Hu, Marcin Golczak, Krzysztof Palczewski, Jianye Zhang |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Retinal degeneration genetic structures medicine.drug_class Metabolite Retinal Pigment Epithelium Biology Mice chemistry.chemical_compound medicine Animals Retinoid Mice Knockout Pharmacology Retina Retinal pigment epithelium Retinal Degeneration Retinal Articles medicine.disease eye diseases medicine.anatomical_structure Biochemistry chemistry RPE65 Retinaldehyde Molecular Medicine Cattle Female sense organs Diterpenes Photic Stimulation Visual phototransduction |
| Zdroj: | Molecular Pharmacology. 87:477-491 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.114.096560 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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