Nuclear Receptor Chemical Reporter Enables Domain-Specific Analysis of Ligands in Mammalian Cells

The
characterization of specific metabolite–protein interactions
is important in chemical biology and drug discovery. For example,
nuclear receptors (NRs) are a family of ligand-activated transcription
factors that regulate diverse physiological processes in animals and
are key targets for therapeutic development. However, the identification
and characterization of physiological ligands for many NRs remains
challenging, because of limitations in domain-specific analysis of
ligand binding in cells. To address these limitations, we developed
a domain-specific covalent chemical reporter for peroxisome proliferator-activated
receptors (PPARs) and demonstrated its utility to screen and characterize
the potency of candidate NR ligands in live cells. These studies demonstrate
targeted and domain-specific chemical reporters provide excellent
tools to evaluate endogenous and exogenous (diet, microbiota, therapeutics)
ligands of PPARs in mammalian cells, as well as additional protein
targets for further investigation.