Prof. Ling Yang’s group has made a breakthrough in drug metabolism research field. Members in Prof. Yang’s group, cooperated with prof. Jingnan Cui of State Key Laboratory of Fine Chemicals, Dalian University of Technology, have designed and developed an innovative highly selective fluorescent probe for human cytochrome P450 1A (CYP1A). The relevant results have been published as a full article entitled “A highly selective ratiometric two-photon fluorescent probe for human cytochrome P450 1A”, which has recently been published online in Journal of the American Chemical Society (http://pubs.acs.org/doi/abs/10.1021/jacs.5b09854).
CYP1A, one of the most important phase I drug-metabolizing enzymes in human, plays an essential role in metabolism of therapeutic drugs and activation of environmental contaminants or other xenobiotics (e.g., aflatoxins) to their ultimate carcinogens. In Mongoloids, the expression and activity of CYP1A are relatively high, which contribute to the tumor formation and thus increase the incidence of some major cancers (liver cancer, lung cancer, and so on). In addition, large inter-individual differences in CYP1A expression and catalytic activity are reported, due to a variety of genetic factors, therapeutic drugs and environmental factors. Thus, developing a practical method for rapid, sensitive detection and real-time monitoring of the enzymatic activity of CYP1A in biological systems will be a major breakthrough for solving these problems and a big challenge in this field.
A highly selective ratiometric two-photon fluorescent probe for human cytochrome P450 1A(Photo by Ziru Dai and Guangbo Ge)
CYP1A is a membrane-bound enzyme, for which the development and application of a highly selective probe are affected by various factors, such as selectivity and ability of resisting biological interference. The probe was designed on the basis of 3D structure information and the key amino acids in the active cavity of CYP1A, while the compound with two-photon absorption properties was selected as the fluorophore. To achieve a highly sensitive and selective probe for CYP1A, a series of derivatives were synthesized and used to explore the potential structure-selectivity relationship, by using a panel of human CYP isoforms for selectivity screening. Furthermore, the probe can be used in ratiometric two-photon imaging of intracellular CYP1A in living cells and tissues for the first time. This newly developed probe can be used to real-time monitor the enzyme activity of CYP1A in complex biological systems, and thus can be used for rapid screening of new drugs at early stage, tissue imaging, in vitro diagnostics and other biomedical fields.
In recent years, Prof. Yang’s group has been making progress in characterizing many important human drug-metabolizing enzymes, for example, a highly selective probe for human cytochrome P450 3A4 (http://pubs.rsc.org/en/Content/ArticleLanding/2013/CC/c3cc45250f); a highly selective ratiometric fluorescent probe for human carboxylesterase 1 (http://www.sciencedirect.com/science/article/pii/S0956566314000670); a highly selective long-wavelength fluorescent probe for human carboxylesterase 2 (http://pubs.rsc.org/en/Content/ArticleLanding/2014/CC/C4CC06642A); and an optimized ratiometric fluorescent probe for human UDP-glucuronosyltransferase 1A1 (http://www.sciencedirect.com/science/article/pii/S0956566315301007). These innovations provide powerful tools for personalized medicine and individualized diagnosis in the fields of translational and precision medicine.
This work was supported by the National S&T Major Projects of China, NSFC, and the National Basic Research Program of China.(Text/Photo by Ziru Dai and Guangbo Ge)