A practical strategy to develop isoform-selective near-infrared fluorescent probes for human cytochrome P450 enzymes

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

Research output: Contribution to journalArticlepeer-review

11 Citations (SciVal)

Abstract

Currently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system. In the second stage of our filtering approach, these candidates were further screened using reverse protein-ligand docking to effectively determine CYP isoenzyme-specific probe(s). Using our double-filtering approach, probes S9 and S10 were successfully developed for the real-time and selective detection of CYP2C9 and CYP2J2, respectively, to facilitate high-throughput screening and assessment of CYP2C9-mediated clinical drug interaction risks and CYP2J2-associated disease diagnosis. These observations suggest that our strategy could be used to develop the isoform-specific probes for CYPs.

Original languageEnglish
Pages (from-to)1976-1986
Number of pages11
JournalActa Pharmaceutica Sinica B
Volume12
Issue number4
Early online date25 Nov 2021
DOIs
Publication statusPublished - 30 Apr 2022

Bibliographical note

Funding Information:
The authors thank the National Natural Science Foundation of China (81930112, 82174228 and 82004211), National Key R&D program of China (2018YFC1705900), Distinguished Professor of Liaoning Province (XLYC2002008, China), “1+X” program for Clinical Competency enhancement-Interdisciplinary Innovation Project of Second Hospital of Dalian Medical University, Dalian Science and Technology Leading Talents Project (2019RD15, China), High-level Talents of Dalian (2020RQ066 and 2020RQ076, China), the Open Research Fund of the School of Chemistry and Chemical Engineering, and Henan Normal University for support (2020ZD01 and 2021YB07, China) for financial support. T.D.J. wishes to thank the Royal Society for a Wolfson Research Merit Award.

Funding Information:
The authors thank the National Natural Science Foundation of China ( 81930112 , 82174228 and 82004211 ), National Key R&D program of China ( 2018YFC1705900 ), Distinguished Professor of Liaoning Province ( XLYC2002008 , China), “1+X” program for Clinical Competency enhancement-Interdisciplinary Innovation Project of Second Hospital of Dalian Medical University , Dalian Science and Technology Leading Talents Project ( 2019RD15 , China), High-level Talents of Dalian ( 2020RQ066 and 2020RQ076 , China), the Open Research Fund of the School of Chemistry and Chemical Engineering , and Henan Normal University for support ( 2020ZD01 and 2021YB07 , China) for financial support. T.D.J. wishes to thank the Royal Society for a Wolfson Research Merit Award.

Publisher Copyright:
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

Keywords

  • Biomarker analysis
  • Cytochrome P450
  • Drug–drug interactions
  • Enzyme activity bioimaging
  • Fluorescent probe

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

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