title: Recent progress in the discovery of natural inhibitors against human carboxylesterases.
abstract: Mammalian carboxylesterases (CEs) are important serine hydrolases catalyzing the hydrolysis of ester- or amide-containing compounds into the corresponding alcohols and carboxylic acids. In human, two primary carboxylesterases including hCE1 and hCE2 have been identified and extensively studied in the past decade. hCE1 is known to play crucial roles in the metabolism of a wide variety of endogenous esters, clinical drugs and insecticides, while hCE2 plays a key role in the metabolic activation of anticancer agents including irinotecan and capecitabine. The key roles of hCEs in both human health and xenobiotic metabolism arouse great interest in the discovery of potent and selective hCEs inhibitors to modulate endobiotic metabolism or to improve the outcomes of patients administrated with ester drugs. This review covers the significance and recent progress in the discovery of natural inhibitors against hCEs. The tools for screening and characterization of inhibitors against human CEs, including traditional LC-based approaches and the newly developed optical substrate-based assays, are summarized and discussed for the first time. Furthermore, the structural information and inhibitory capacities of all reported hCEs inhibitors including fatty acids, flavonoids, tanshinones and triterpenoids have been systematically summarized. All information and knowledge presented in this review will be very helpful for medicinal chemists to develop more potent and highly selective inhibitors against hCEs for potential biomedical applications.
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China; Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China; Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Zou
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Dalian Medical University, Dalian 116044, China. Electronic address: houjie@dlmedu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: geguangbo@dicp.ac.cn.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification; D043182:Carboxylesterase / Q000037:antagonists & inhibitors; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D004952:Esters / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D004952:Esters; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase
keywords: Carboxylesterases; High-throughput screening; Natural inhibitors; hCE1; hCE2