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Vincent M Monnier, Sean Wong, Huasheng Zhou, Xingjun Fan; Screening of FDA approved drugs for their ability to inhibit or worsen hydrogen peroxide mediated aggregation of calf lens crystallins. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4972.
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Age-related cataract is associated with oxidant stress. We recently reported that oxidative crystallin damage due to disulfide bond formation occurs at similar sites in human cataracts and lens crystallins from GSH deficient, cataract prone LEGSKO mouse which can be mimicked by incubation with H2O2. We hypothesize that drugs that prevent or augment oxidative damage may delay or worsen cataract progression, respectively.
An HTS assay for discovery of drugs that can block or worsen oxidative stress mediated aggregation of calf lens gamma crystallins purified by Sephadex G-200 gel filtration (Ortwerth et al.,Exp Eye Res. 1988;47:155-68). The assay consists of 90 ul crystallin solution (~5mg/ml) incubated for 24-48hrs with 1-5 ul of drugs (2.5-25 uM) in DMSO from the 2008 Microsource Discovery library of small molecule compounds and 10ul of H2O2 (10 mM). A total of 13 plates (1040 compounds) were tested.
Absorbance at 420 nm and fine print read-through were used as readouts. 166 hits were obtained.117 (11%) and 49 (5%) compounds gave better and worse transparency results, respectively. Upon retesting under drastic conditions of sterility 22% of compounds tested reproducibly better and 24.5% worse. 49 compounds (31 better, 14 worse, 4 equivocal) belonged to the following drug categories (Better/Worse): antibacterial (13/3), antineoplastic/anti-inflammatory(4/1), psychotropic (6/3), vaso/cardioactive (4/3), others (3/3). Altogether, 6 top hit compounds dramatically improved readability of fine print. Among those that worsened transparency are amiodarone, quinacrine and thiothixene. The first two are associated with high cataract prevalence in the Blue Mountain Eye Study. Surprisingly, hydrocortisone, a known risk factor for cataract, improved aggregation possibly by acting like a sterol or antioxidant. One of the most powerful inhibitors arising from this screen is an aspergillus/ penicillium mycotoxin.
A preliminary screen revealed candidate compounds that may block or worsen oxidant stress related crystallin aggregation in cataracts. Collaborative cutting edge efforts on repositioning of FDA approved drugs toward cataract prevention are in progress with Dr. Rong Xu, a computational expert and NIH innovator award recipient for “Rapid Reverse Translational Drug Repositioning Strategies”.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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