Xia Lv, Yangliu Xia, Moshe Finel, Jingjing Wu, Guangbo Ge, Ling Yang. Recent progress and challenges in screening and characterization of UGT1A1 inhibitors[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 258-278

Recent progress and challenges in screening and characterization of UGT1A1 inhibitors
Xia Lva,b, Yangliu Xiac, Moshe Fineld, Jingjing Wuc, Guangbo Gea,c, Ling Yanga
a Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
b Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, College of Life Science, Dalian Minzu University, Dalian 116600, China;
c Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;
d Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland
Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb-drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1-ligand interactions.
Key words:    UGT1A1 inhibitors    Drug/herbdrug interactions    Probe substrates    High-throughput screening   
Received: 2018-06-08     Revised: 2018-08-16
DOI: 10.1016/j.apsb.2018.09.005
Funds: This work was supported by the NSF of China (81773687,81703606,81573501,81473181),the National Key Research and Development Program of China (2017YFC1700200 and 2017YFC1702000),the Fundamental Research Funds for the Central Universities (wd01185),and the National S&T Major Projects of China (2017ZX09101004),Program of Shanghai Academic/Technology Research Leader (18XD1403600),the Innovative Entrepreneurship Program of High-level Talents in Dalian (2016RQ025&2017RQ121),and the Doctoral Scientific Research Foundation of Liaoning Province,China (20170520059).
Corresponding author: Guangbo Ge
Author description:
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Xia Lv
Yangliu Xia
Moshe Finel
Jingjing Wu
Guangbo Ge
Ling Yang

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