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Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold

文献类型：期刊论文

作者Han, Sheng6; Li, Heng1,5; Chen, Weixiong4; Yang, Li5; Tong, Xiankun5; Zuo, Jianping2,5; Hu, Youhong3,4,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-10-05
卷号240页码:12
关键词Ebola virus Entry inhibitor Structural optimization
ISSN号0223-5234
DOI10.1016/j.ejmech.2022.114608
通讯作者Tong, Xiankun(xktong@simm.ac.cn) ; Zuo, Jianping(jpzuo@simm.ac.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要Ebola virus (EBOV), one member of the family Filoviridae, can causes hemorrhagic fever and other severe diseases in humans with a high mortality rate (25-90%). Until recently, there were no approved drugs and very limited treatment method for Ebola virus disease. In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50 = 0.05 mu M, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50 = 0.17 mu M, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of the new chemical scaffold provided more information on the binding modes and the spare volume at the binding cavity, thus can guide the design of the further potent compounds.
WOS关键词HIV-PROTEASE INHIBITORS ; BIOLOGICAL EVALUATION ; VIRUS ; DERIVATIVES ; IDENTIFICATION
资助项目National Natural Science Foundation of P. R. China[81872725] ; National Natural Science Foundation of P. R. China[22107108] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; China Postdoctoral Science Foundation[2021M693269]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000855284600001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/302464]  
专题新药研究国家重点实验室
通讯作者Tong, Xiankun; Zuo, Jianping; Hu, Youhong
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China
3.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Xiangshanzhi Rd, Hangzhou 310024, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Immunol Dis Res Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Han, Sheng,Li, Heng,Chen, Weixiong,et al. Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,240:12.
APA Han, Sheng.,Li, Heng.,Chen, Weixiong.,Yang, Li.,Tong, Xiankun.,...&Hu, Youhong.(2022).Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,240,12.
MLA Han, Sheng,et al."Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 240(2022):12.

入库方式： OAI收割

来源：上海药物研究所

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