Dynamic Ir(III) Photosensors for the Major Human Drug-Metabolizing Enzyme Cytochrome P450 3A4
Year: 2023
Type: article
Abstract: Probing the activity of cytochrome P450 3A4 (CYP3A4) is critical for monitoring the metabolism of pharmaceuticals and identifying drug–drug interactions. A library of Ir(III) probes that detect occupancy of the CYP3A4 active site were synthesized and characterized. These probes show selectivity for CYP3A4 inhibition, low cellular toxicity, K d values as low as 9 nM, and are highly emissive with lifetimes up to 3.8 μs in cell growth media under aerobic conditions. These long emission lifetimes allow for time-resolved gating to distinguish probe from background autofluorescence from growth media and live cells. X-ray crystallographic analysis revealed structure–activity relationships and the preference or indifference of CYP3A4 toward resolved stereoisomers. Ir(III)-based probes show emission quenching upon CYP3A4 binding, then emission increases following displacement with CYP3A4 inhibitors or substrates. Importantly, the lead probes inhibit the activity of CYP3A4 at concentrations as low as 300 nM in CYP3A4-overexpressing HepG2 cells that accurately mimic human hepatic drug metabolism. Thus, the Ir(III)-based agents show promise as novel chemical tools for monitoring CYP3A4 active site occupancy in a high-throughput manner to gain insight into drug metabolism and drug–drug interactions.
Source: Inorganic Chemistry
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Energy, Wayne State University, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, Division of Chemistry, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1181855182, G1229526393, G1286236842, G1286251239, G1337544421, G1451874870, G1863003419, G2171580583, G223002938, G2371548206, G2539837713, G262532246, G303061748, G30714459, G3083819904, G315621713, Tailoring Structures of Sulfated Oligosaccharides for Modulating Heparanase Activity, Control of Excited State Dynamics of Ru(II) Complexes for Dual Activity, G382641700, 500 MHz NMR Spectrometer, G419881185, G4235786860, G4263269543, G42916606, G4501827968, G4581610328, Center for Urban Responses to Environmental Stressors (CURES), G495301720, G498139845, G4989152402, G5094606986, G5570207115, G650090426, G6550344761, G7283024673, Theoretical and Experimental Investigations of Photoheterolysis Reactions, G7396808078, G7526285082, G7619734671, G7787287669, G7863156295, G8114311459, G8382000481, G8925327636, Chemistry Biology Interface Training Program at Wayne State University, A Synchrotron Radiation Structural Biology Resource, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Toxicological importance of CYP3A4 catalysis and inhibition, G911061179, G969889393
OpenAlex ID: W4319662736