Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 4, Pages 1999-2007Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01568
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Funding
- NIH [GM20501-42]
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Assaying lipolytic enzymes is extremely challenging because they act on water-insoluble lipid substrates, which are normally components of micelles, vesicles, and cellular membranes. We extended a new lipidomics-based liquid chromatographic-mass spectrometric assay for phospholipases A(2) to perform inhibition analysis using a variety of commercially available synthetic and natural phospholipids as substrates. Potent and selective inhibitors of three recombinant human enzymes, including cytosolic, calcium-independent, and secreted phospholipases A(2) were used to establish and validate this assay. This is a novel use of dose-response curves with a mixture of phospholipid substrates, not previously feasible using traditional radioactive assays. The new application of lipidomics to developing assays for lipolytic enzymes revolutionizes in vitro testing for the discovery of potent and selective inhibitors using mixtures of membranelike substrates.
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