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Angelica Harper, Tim Mather, Anh Le, Anthony Burgett, Gennadiy P Moiseyev, John Moore, Jody A Summers Rada; Characterization of a novel retinaldehyde dehydrogenase selective inhibitor. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Despite continued research on the regulation of eye size and refraction, no pharmaceutical approaches have proven effective in deterring the progression of myopia. Recently, retinaldehyde dehydrogenase 2 (RALDH2) has been identified as a potential therapeutic target for the control of postnatal ocular growth. The objective in the present study was to use an intelligent-drug design approach to develop a RALDH2-selective inhibitor to further examine the role of RALDH2 in myopia.
MoleGro virtual docking software was used to dock the theoretical structure of dichloro-all-trans-retinone (DAR) into structural models of chick RALDH2 and human ALDH2. DAR was synthesized by a modified dihalomethyllithium approach. Selectivity of DAR was determined in vitro using NADH assays with recombinant RALDH2 and hu-ALDH2. The effect of DAR on retinoic acid (RA) synthesis in choroidal lysates was determined by an in vitro RA synthesis assay with HPLC quantification of synthesized RA. Toxicity on scleral tissue was measured with a proteoglycan (PG) synthesis assay.
Docking of the theoretical structure of DAR suggested selectivity to RALDH2 (MolDock score: -71.92±6.83) compared to hu-ALDH2 (MolDock score: 14.41±17.98). In vitro fluorescence assays indicated that DAR inhibited RALDH2 activity in a dose dependent manner (25% inhibition with 10 uM, p< 0.01; 48% inhibition with 50 uM, p< 0.001). DAR had no significant inhibitory effect on hu-ALDH2 activity. Further, 5 μM DAR significantly inhibited RA synthesis in choroidal lysates isolated from chick eyes recovering from induced myopia (p< 0.01; n=4). When toxicity of DAR was examined on scleral tissue, 10 μM DAR was less inhibitory on PG synthesis as compared with a non-specific inhibitor (WIN 18446) at the same concentration (p< 0.05; n=10).
We have developed a RALDH-selective inhibitor, dichloro-all-trans-retinone. The results obtained from this study will allow us to further investigate the role of RALDH2 in postnatal eye growth through future in vitro and in vivo studies and may lead to the development of an effective inhibitor to slow the progression of myopia.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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