Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics

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 miconazolean
antifungal drug that attenuates disease severity in preclinical models
of multiple sclerosisinhibits 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.