单位：[a]Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China[b]National Institute for the Control of Pharmaceutical and Biological Products, Beijing 100050, China[c]Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China临床科室神经内科神经内科首都医科大学附属北京友谊医院
Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal drug-like feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism. (C) 2018 Elsevier Masson SAS. All rights reserved.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81673307, 81621064]; CAMS Innovation Fund for Medical Sciences [2016-I2M-3-009]
第一作者单位：[a]Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
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推荐引用方式(GB/T 7714)：
Xin Zhang,Qiang Liu,Na Zhang,et al.Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage[J].EUROPEAN JOURNAL of MEDICINAL CHEMISTRY.2018,149:45-55.doi:10.1016/j.ejmech.2018.02.061.
APA：
Xin Zhang,Qiang Liu,Na Zhang,QianeQian Li,ZhaneDong Liu...&DaneQing Song.(2018).Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage.EUROPEAN JOURNAL of MEDICINAL CHEMISTRY,149,
MLA：
Xin Zhang,et al."Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage".EUROPEAN JOURNAL of MEDICINAL CHEMISTRY 149.(2018):45-55
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