Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy. (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. Volume 131:Number 29(2019)
• Page Start: 10064
• Page End: 10068
• Publication Date: 2019-06-11
• Subjects: Analytische Methoden -- Cytochrom P450 3A4 -- Enzym-aktivierbare Sonden -- Fluoreszenzsonden -- Molekulares Design; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201903683
• Languages: English
• ISSNs: 0044-8249

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 : Nimm 2 : Eine hochempfindliche, CYP3A4‐spezifische Zwei‐Photonen‐Fluoreszenzsonde wurde auf Basis einer 2D‐Designstrategie entworfen, die ensemblebasiertes virtuelles Screening mit rationaler Strukturmodifizierung kombiniert. Die Sonde ermöglicht den Nachweis der CYP3A4‐Aktivität in Lebendzellen, Geweben und Zebrafischen und erleichtert so die Bewertung von Risiken infolge CYP3A4‐vermittelter Wirkstoff‐Wirkstoff‐Wechselwirkungen.