UPro1A8: A Specific Fluorescent Probe for Functional Imaging and Inhibitor Screening of UGT1A8
Xin-Fang Zhai1,2, Jing-Jing Fan1, Yang Yi1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
Journal of Medicinal Chemistry
|April 4, 2026
Summary
Researchers developed UPro1A8, the first fluorescent probe for UDP-glucuronosyltransferase 1A8 (UGT1A8). This tool enables real-time monitoring of UGT1A8 activity, aiding cancer research and drug interaction studies.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- UDP-glucuronosyltransferase 1A8 (UGT1A8) is a crucial phase II metabolic enzyme implicated in endometrial and breast cancer pathogenesis.
- The precise roles of UGT1A8 in drug-drug interactions and disease mechanisms are not fully understood due to a lack of selective real-time monitoring tools.
Purpose of the Study:
- To develop a novel fluorescent probe for selective and real-time detection of UGT1A8 activity.
- To utilize this probe for evaluating UGT1A8 inhibitors and advancing functional studies.
Main Methods:
- Designed and synthesized UPro1A8, an "off-on" fluorescent probe using a single-end modification strategy.
- Validated the probe's selectivity and sensitivity for UGT1A8 against other UGT isoforms.
- Applied UPro1A8 for real-time visualization of endogenous UGT1A8 activity in living cells, tissue slices, and zebrafish.
- Screened a compound library to identify UGT1A8 inhibitors using the developed probe.
Main Results:
- UPro1A8 exhibited excellent selectivity and sensitivity for UGT1A8.
- The probe successfully enabled real-time visualization of UGT1A8 activity in various biological systems.
- Four natural products—Ginkgetin, Silibinin, Ledebouriellol, and Antcin C (R)—were identified as potent UGT1A8 inhibitors.
Conclusions:
- UPro1A8 is the first selective "off-on" fluorescent probe for UGT1A8.
- This probe serves as a robust molecular tool for advancing functional studies of UGT1A8.
- The findings facilitate precise inhibitor evaluation and deepen the understanding of UGT1A8's role in diseases and drug metabolism.
