cellular and biophysical pipeline for the screening of peroxisome proliferator-activated receptor beta/delta agonists: avoiding false positives

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ID: 153478
2018
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Abstract
Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits. All of the assays were validated using well-known commercial agonists providing trustworthy data. Furthermore, to validate and test this pipeline, we screened a natural extract library (560 extracts), and we found one plant extract that might be interesting for PPARß/δ modulation. In conclusion, our results suggested that we developed a cheaper and more robust pipeline that goes beyond the single activation screening, as it also evaluates PPARß/δ tertiary structure stabilization and the ligand affinity constant, selecting only molecules that directly bind to the receptor. Moreover, this approach might improve the effectiveness of the screening for agonists that target PPARß/δ for drug development.
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videira2018pparcellular Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Natália Bernardi Videira;Fernanda Aparecida Heleno Batista;Artur Torres Cordeiro;Ana Carolina Migliorini Figueira
Journal Life (Basel, Switzerland)
Year 2018
DOI
10.1155/2018/3681590
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