Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy. Issue 29 (11th June 2019)

• Record Type: Journal Article
• Authors: Ning, Jing; Wang, Wei; Ge, Guangbo; Chu, Peng; Long, Feida; Yang, Yongliang; Peng, Yulin; Feng, Lei; Ma, Xiaochi; James, Tony D.
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 29(2019)
• Page Start: 9959
• Page End: 9963
• Publication Date: 2019-06-11
• Subjects: analytical methods -- cytochrome P450 3A4 -- enzyme-activatable probes -- fluorescent probes -- molecular design; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201903683
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Selective two‐photon CYP3A4 probe : A highly sensitive two‐photon fluorescent probe specific for CYP3A4 was designed based on a two‐dimensional design strategy that combines ensemble‐based virtual screening with rational structure modification. The probe allows the detection of CYP3A4 activity in living cells, tissue, and zebrafish, facilitating the evaluation of risks from CYP3A4‐mediated drug–drug interactions in the clinic.