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

doi:10.1002/anie.202113191

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

Department of Chemistry

Research output: Contribution to journal › Comment/debate › peer-review

22 Citations (SciVal)

221 Downloads (Pure)

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 language	English
Article number	e202113191
Journal	Angewandte Chemie - International Edition
Volume	61
Issue number	5
Early online date	1 Dec 2021
DOIs	https://doi.org/10.1002/anie.202113191
Publication status	Published - 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.

Funding

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
General Chemistry

Access to Document

10.1002/anie.202113191

3A MBI 1129-author accepted version
This is the peer reviewed version of the following article: J. Ning, Z. Tian, J. Wang, B. Wang, X. Tian, Z. Yu, X. Huo, L. Feng, J. Cui, T. D. James, X. Ma, Angew. Chem. Int. Ed. 2022, 61, e202113191., which has been published in final form at https://doi.org/10.1002/anie.202113191. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Accepted author manuscript, 869 KB

Cite this

@article{71a6ade60bf946b1b3d24b911053c454,

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

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.",

keywords = "Analytical methods, Cytochrome P450 3A, Fluorescent probes, Mechanism-based inactivation, Rational molecular design",

author = "Jing Ning and Zhenhao Tian and Jiayue Wang and Bo Wang and Xiangge Tian and Zhenlong Yu and Xiaokui Huo and Lei Feng and Jingnan Cui and James, {Tony D.} and Xiaochi Ma",

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. ",

year = "2022",

month = jan,

day = "26",

doi = "10.1002/anie.202113191",

language = "English",

volume = "61",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "John Wiley and Sons Inc.",

number = "5",

}

TY - JOUR

T1 - Rational Design of a Two-Photon Fluorescent Probe for Human Cytochrome P450 3A and the Visualization of Mechanism-Based Inactivation

AU - Ning, Jing

AU - Tian, Zhenhao

AU - Wang, Jiayue

AU - Wang, Bo

AU - Tian, Xiangge

AU - Yu, Zhenlong

AU - Huo, Xiaokui

AU - Feng, Lei

AU - Cui, Jingnan

AU - James, Tony D.

AU - Ma, Xiaochi

N1 - 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.

PY - 2022/1/26

Y1 - 2022/1/26

N2 - 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.

AB - 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.

KW - Analytical methods

KW - Cytochrome P450 3A

KW - Fluorescent probes

KW - Mechanism-based inactivation

KW - Rational molecular design

UR - http://www.scopus.com/inward/record.url?scp=85121378496&partnerID=8YFLogxK

U2 - 10.1002/anie.202113191

DO - 10.1002/anie.202113191

M3 - Comment/debate

AN - SCOPUS:85121378496

SN - 1433-7851

VL - 61

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 5

M1 - e202113191

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this