Optical substrates for drug-metabolizing enzymes: Recent advances and future perspectives

Abstract

Drug-metabolizing enzymes (DMEs), a diverse group of enzymes responsible for the metabolic elimination of drugs and other xenobiotics, have been recognized as the critical determinants to drug safety and efficacy. Deciphering and understanding the key roles of individual DMEs in drug metabolism and toxicity, as well as characterizing the interactions of central DMEs with xenobiotics require reliable, practical and highly specific tools for sensing the activities of these enzymes in biological systems. In the last few decades, the scientists have developed a variety of optical substrates for sensing human DMEs, parts of them have been successfully used for studying target enzyme(s) in tissue preparations and living systems. Herein, molecular design principals and recent advances in the development and applications of optical substrates for human DMEs have been reviewed systematically. Furthermore, the challenges and future perspectives in this field are also highlighted. The presented information offers a group of practical approaches and imaging tools for sensing DMEs activities in complex biological systems, which strongly facilitates high-throughput screening the modulators of target DMEs and studies on drug/herb‒drug interactions, as well as promotes the fundamental researches for exploring the relevance of DMEs to human diseases and drug treatment outcomes.

Keywords: Drug-metabolizing enzymes (DMEs); Fluorescence-based assay; High-throughput screening; Optical substrates.

Graphical abstract

Figure 1

Design strategy for constructing CES optical substrates and the representative optical substrates.

Figure 2

Design strategies for constructing CYP substrates and the representative optical substrates.

Figure 3

Design strategies for constructing the fluorescent substrates for MAOs and the representative probes.

Figure 4

Design strategy for constructing the fluorescent substrates for ALDHs and the representative probes.

Figure 5

Design strategies for constructing the fluorescent substrates for NQOs and the representative probes.

Figure 6

Design strategies of GSTs fluorescent substrate and representative probes.

Figure 7

In situ imaging of target DME in living systems. (A) Confocal fluorescence images of U87-MG cells with COMT-F10. Reproduced with permission from Ref. , copyright © 2017, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Two-photon confocal fluorescent images of endogenous CES2A in a mouse liver slice stained by CES2A-F5. Reproduced with permission from Ref. , copyright © 2015, American Chemical Society. (C) Representative fluorescence images of visualizing CES2A levels in nude mice using CES2A-F6. Reproduced with permission from Ref. , copyright © 2016, Elsevier B.V. (D) Biological imaging of CES1A activity in zebrafish by using CES1A-F3. Reproduced with permission from Ref. , copyright © 2018, Elsevier B.V.

Figure 8

A bioluminescent substrate reveals that CES1A is a novel serologic indicator for hepatocyte injury.