Rational Design of a Two-Photon Fluorescent Probe for Human Cytochrome P450 3A and the Visualization of Mechanism-Based Inactivation

Jing Ning, Zhenhao Tian, Jiayue Wang, Bo Wang, Xiangge Tian, Zhenlong Yu, Xiaokui Huo, Lei Feng, Jingnan Cui, Tony D. James, Xiaochi Ma

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Abstract

Mechanism-based inactivation (MBI) can mediate adverse reactions and hepatotoxicity from drugs, which is a result of their conversion into highly reactive metabolites catalyzed by enzymes such as cytochrome P450 3A (CYP3A). In the present research, we optimized the key interaction domain of the fluorophore with the target protein to develop a two-photon fluorescent probe for CYP3A that is involved in the metabolism of more than half of all clinical drugs. The developed BN-1 probe exhibited appropriate selectivity and sensitivity for the semi-quantitative detection and imaging of endogenous CYP3A activity in various living systems, thereby providing a high-throughput screening system enabling evaluation of MBI-associated hepatotoxicity by CYP3A. Using BN-1 as a fluorescent molecular tool facilitates the efficient discovery and characterization of CYP3A-induced MBI in natural systems.

Original languageEnglish
Article numbere202113191
JournalAngewandte Chemie - International Edition
Volume61
Issue number5
Early online date1 Dec 2021
DOIs
Publication statusPublished - 26 Jan 2022

Bibliographical note

Funding Information:
The authors thank the National Natural Science Foundation of China (82174228 and 82004211), National Key R&D program of China (2018YFC1705900), Distinguished professor of Liaoning Province (XLYC2002008), Dalian Science and Technology Leading Talents Project (2019RD15), “1+X” program for Clinical Competency enhancement‐Interdisciplinary Innovation Project of Second Hospital of Dalian Medical University, High‐level Talents of Dalian (2020RQ066 and 2020RQ076) and the open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University for support (2020ZD01 and 2021YB07) for financial support. T.D.J. wishes to thank the Royal Society for a Wolfson Research Merit Award. The authors also thank Wei Yang (Chemical Analysis and Research Center at DUT) for the generous help in fluorescence imaging.

Keywords

  • Analytical methods
  • Cytochrome P450 3A
  • Fluorescent probes
  • Mechanism-based inactivation
  • Rational molecular design

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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