UPro^1A8: A Specific Fluorescent Probe for Functional Imaging and Inhibitor Screening of UGT1A8

UDP-glucuronosyltransferase 1A8 (UGT1A8), a key human phase II metabolic enzyme, is related to the pathogenesis of endometrial and breast cancers. Nevertheless, its roles in drug-drug interactions and disease mechanisms remain unclear due to the lack of selective real-time monitoring tools. In this work, we developed UPro^1A8, the first "off-on" fluorescent probe specifically targeting UGT1A8, designed via a "single-end modification strategy". UPro^1A8 demonstrates excellent selectivity and sensitivity for UGT1A8 over other UGT isoforms. It enables real-time visualization of endogenous UGT1A8 activity in living cells, tissue slices, and zebrafish, providing a flexible platform for precise inhibitor evaluation. Screening of a compound library using this probe identified four natural products, namely Ginkgetin, Silibinin, Ledebouriellol, and Antcin C (R), as potent UGT1A8 inhibitors. Collectively, these findings position UPro^1A8 as a robust molecular tool for advancing UGT1A8 functional studies.