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High content screening for nonclassical peroxisome proliferators
Jonathan Z Sexton1,2, Qingping He1, Lawrence J Forsberg3, Jay E Brenman3,4
1Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, 2Department of Pharmaceutical Sciences, North Carolina Central University, 3The Neuroscience Center UNC Chapel Hill School of Medicine, 4Cell and Developmental Biology Dept UNC-CH School of Medicine
Abstract: Peroxisomes are ubiquitous cellular organelles that perform vital functions including fatty acid beta-oxidation, plasmalogen synthesis, and detoxification of harmful oxidative species. In rodents numerous compounds that increase peroxisome biogenesis also alleviate metabolic syndrome (MetS)/type 2 diabetes (T2D) symptoms. However, compounds that increase peroxisome biogenesis in rodents largely do not increase peroxisome biogenesis in humans. We designed a novel genetically encoded high throughput screening (HTS) high content assay to identify small molecule compounds that function as peroxisome proliferators in human cells. From this assay we have confirmed that 4-phenylbutyrate (PBA), a PPAR independent peroxisome proliferator and chemical chaperone, increases peroxisome proliferation in human cells and serves as a positive control for our screen. We performed a small pilot and larger 15,000 compound production screen with an overall Z’ factor of 0.74 for 384-well plate format, providing a valuable screening tool for identifying peroxisome modulator compounds. From this screen we have identified 4 existing drugs and 10 novel compounds, some with common scaffolds 1000X more potent than PBA. It is hoped that these novel compounds may serve as scaffolds for testing for efficacy in alleviating MetS/T2D symptoms both in mouse models and ultimately human disease.
Keywords: high-content screening, high-content analysis, peroxisome biogenesis, diabetes, metabolic syndrome, 4-phenylbutyrate
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