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Publication Abstract from PubMed

Cytochromes P450 (CYPs) are a superfamily of enzymes responsible for biosynthesis and drug metabolism. Monitoring the activity of CYP3A4, the major human drug-metabolizing enzyme, is vital for assessing the metabolism of pharmaceuticals and identifying harmful drug-drug interactions. Existing probes for CYP3A4 are irreversible turn-on substrates that monitor activity at specific time points in end-point assays. To provide a more dynamic approach, we designed, synthesized, and characterized emissive Ir(III) and Ru(II) complexes that allow monitoring of the CYP3A4 active-site occupancy in real time. In the bound state, probe emission is quenched by the active-site heme. Upon displacement from the active site by CYP3A4-specific inhibitors or substrates, these probes show high emission turn-on. Direct probe binding to the CYP3A4 active site was confirmed by X-ray crystallography. The lead Ir(III)-based probe has nanomolar Kd and high selectivity for CYP3A4, efficient cellular uptake, and low toxicity in CYP3A4-overexpressing HepG2 cells.

Ir(III)-Based Agents for Monitoring the Cytochrome P450 3A4 Active Site Occupancy.,Denison M, Steinke SJ, Majeed A, Turro C, Kocarek TA, Sevrioukova IF, Kodanko JJ Inorg Chem. 2022 Aug 22. doi: 10.1021/acs.inorgchem.2c02587. PMID:35994607^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.