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Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy
Author(s) -
Ning Jing,
Wang Wei,
Ge Guangbo,
Chu Peng,
Long Feida,
Yang Yongliang,
Peng Yulin,
Feng Lei,
Ma Xiaochi,
James Tony D.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201903683
Subject(s) - fluorophore , cyp3a4 , chemistry , gene isoform , fluorescence , cytochrome p450 , selectivity , enzyme , computational biology , biochemistry , biology , catalysis , physics , quantum mechanics , gene
Abstract The rapid development of fluorescent probes for monitoring target enzymes is still a great challenge owing to the lack of efficient ways to optimize a specific fluorophore. Herein, a practical two‐dimensional strategy was designed for the development of an isoform‐specific probe for CYP3A4, a key cytochrome P450 isoform responsible for the oxidation of most clinical drugs. In first dimension of the design strategy, a potential two‐photon fluorescent substrate ( NN ) for CYP3A4 was effectively selected using ensemble‐based virtual screening. In the second dimension, various substituent groups were introduced into NN to optimize the isoform‐selectivity and reactivity. Finally, with ideal selectivity and sensitivity, NEN was successfully applied to the real‐time detection of CYP3A4 in living cells and zebrafish. These findings suggested that our strategy is practical for developing an isoform‐specific probe for a target enzyme.