NDLI: A practical strategy to design and develop an isoform-specific fluorescent probe for a target enzyme: CYP1A1 as a case study

Content Provider	Royal Society of Chemistry (RSC)
Author	Ning, Jing Cui, Jing-Nan Yu, Yang Li, Yan Dai, Zi-Ru Ge, Guang-Bo Feng, Lei Jin, Qiang Cheng, Hailing Yang, Ling
Copyright Year	2017
Abstract	The development of isoform-specific probe(s) for a target enzyme with multiple homologs is always challenging. Herein, a practical strategy was used to design and develop an isoform-specific probe for CYP1A1, a key cytochrome P450 isoenzyme involved in xenobiotic metabolism and bioactivation. On the basis of the subtle differences in 3D structure and substrate preference between CYP1A1 and its homolog CYP1A2, we proposed that it was possible to design a CYP1A1-specific probe via local modification of the reaction site on known CYP1A substrates. To validate this hypothesis, 4-hydroxy-1,8-naphthalimide (HN) was selected as the basic fluorophore due to its excellent optical properties, while a series of O-alkylated HN derivatives were prepared to evaluate their specificity towards CYP1A1. Our results revealed that the introduction of a chloroethyl to HN could get the best isoform selectivity towards CYP1A1 over other CYPs including CYP1A2. The newly developed probe NBCeN exhibited excellent specificity, high sensitivity, and a ratiometric fluorescence response following CYP1A1-catalyzed O-dechloroethylation. NBCeN was successfully used to real-time monitor the activity of CYP1A1 in complex biological samples and to rapidly screen CYP1A1 modulators in living systems. NBCeN could also be used for two-photon imaging of intracellular CYP1A1 in living cells and tissues with high ratiometric imaging resolution and deep tissue penetration. All these findings demonstrated that local modification of non-specific substrates was a practical strategy to develop an isoform-specific probe for a target isoenzyme, while NBCeN could serve as a specific imaging tool to explore the biological functions of CYP1A1 in complex biological systems.
Starting Page	2795
Ending Page	2803
Page Count	9
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	8
Issue Number	4
Journal	Chemical Science
DOI	10.1039/c6sc03970g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Fluorophore Enzyme Cytochrome P450, family 1, member A1 Isozyme Cytochrome P450 CYP1A2 Drug metabolism Fluorescence Three-dimensional space
Content Type	Text
Resource Type	Article
Subject	Chemistry

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