Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics
datasetposted on 2017-09-20, 19:10 authored by Kenneth M. Lum, Yoshiaki Sato, Brittney A. Beyer, Warren C. Plaisted, Justin L. Anglin, Luke L. Lairson, Benjamin F. Cravatt
Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid–protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms. We identify the prostaglandin-regulatory enzyme PTGR2 as a target of the antidiabetic hops derivative KDT501 and show that miconazolean antifungal drug that attenuates disease severity in preclinical models of multiple sclerosisinhibits SGPL1, an enzyme that degrades the signaling lipid sphingosine-1-phosphate, drug analogues of which are used to treat multiple sclerosis in humans. Our findings highlight the versatility of lipid-based chemical proteomics probes for mapping small molecule–protein interactions in human cells to gain mechanistic understanding of bioactive compounds.
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lipid-based chemical proteomic probesmass spectrometrylipid sphingosine -1-phosphate drug analoguescell biologyprostaglandin-regulatory enzyme PTGR 2Mapping Proteinproduct derivativesbioactive compoundsSGPLLipid-Based Chemical Proteomics LipidsmoleculeKDT 501lipid-based chemical proteomics probesattenuates disease severityinteractionsclerosisrepurposed drugsphotoreactive lipid probes