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Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach

文献类型：期刊论文

作者Huang, Fubao2,3; Hu, Hangchen3,4,5; Wang, Kai2,3; Peng, Chengyuan3; Xu, Wenwei3; Zhang, Yu3; Gao, Jing3,4; Liu, Yishen1; Zhou, Hu3,4; Huang, Ruimin3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-07-09
卷号63期号:13页码:7052-7065
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c00372
通讯作者Shen, Jianhua(jhshen@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.
WOS关键词BARRIER PERMEABILITY ; A(2) ; DARAPLADIB ; DISCOVERY ; ACETYLHYDROLASE ; ANALOGS ; EVENTS ; DESIGN ; POTENT ; MODEL
资助项目National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[81673302] ; National Key R&D Program of China[2016YFA0502301] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' China[2018ZX09711002-1082 006-014]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000550753700030
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/292124]  
专题新药研究国家重点实验室
通讯作者Shen, Jianhua; Xu, Yechun
作者单位1.Nanchang Univ, Nanchang 330031, Jiangxi, Peoples R China
2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai Adv Res Inst, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Fubao,Hu, Hangchen,Wang, Kai,et al. Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(13):7052-7065.
APA Huang, Fubao.,Hu, Hangchen.,Wang, Kai.,Peng, Chengyuan.,Xu, Wenwei.,...&Xu, Yechun.(2020).Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.JOURNAL OF MEDICINAL CHEMISTRY,63(13),7052-7065.
MLA Huang, Fubao,et al."Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach".JOURNAL OF MEDICINAL CHEMISTRY 63.13(2020):7052-7065.

入库方式： OAI收割

来源：上海药物研究所

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