药学学报, 2019, 54(9): 1612-1619
引用本文:
陈勍, 陈盼盼, 莘一婧, 唐克, 张晓雨, 郭颖. 新属种丝状病毒勐腊病毒进入模型的建立及阻断剂研究[J]. 药学学报, 2019, 54(9): 1612-1619.
CHEN Qing, CHEN Pan-pan, XIN Yi-jing, TANG Ke, ZHANG Xiao-yu, GUO Ying. Establishment of a new genus of filovirus (Mengla virus) entry evaluating system and entry inhibitors discovery[J]. Acta Pharmaceutica Sinica, 2019, 54(9): 1612-1619.

新属种丝状病毒勐腊病毒进入模型的建立及阻断剂研究
陈勍, 陈盼盼, 莘一婧, 唐克, 张晓雨, 郭颖
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 新药作用机制研究与药效评价北京市重点实验室, 北京 100050
摘要:
勐腊病毒(Mengla virus,MLAV)是我国分离的一种源自蝙蝠的丝状病毒,该病毒于2019年被鉴定为丝状病毒新属种,即丝状病毒科滇丝病毒属勐腊病毒。丝状病毒科成员众多,其中埃博拉病毒(Ebola virus,EBOV)和马尔堡病毒(Marburg virus,MARV)恶性程度最高,死亡率24%~90%。系统遗传学研究显示,在丝状病毒家族中,MLAV与MARV亲缘关系较近。MLAV依靠囊膜表面糖蛋白(glycoprotein,GP)进入宿主,重组病毒研究显示其具有蝙蝠-人跨种传播潜力。本课题构建了以GP介导的MLAV进入模型,考察了MLAV对不同组织来源的人源细胞和非洲绿猴肾细胞的感染性,并通过对4个体外可阻断EBOV和MARV进入,且体内药效学证实可显著降低EBOV感染小鼠死亡率的化合物(氯喹、粉防己碱、克罗米芬和托瑞米芬)进行阻断MLAV进入宿主细胞的活性评价。结果显示,氯喹可有效阻断MLAV进入(半数有效浓度EC50:1.56 μmol·L-1),与抗EBOV和MARV活性相当。目前尚无针对MLAV药物研究的相关报道,本研究发现了氯喹具有抑制MLAV进入宿主细胞的能力,将为抗新型丝状病毒药物研究提供参考。
关键词:    勐腊病毒      丝状病毒      进入      氯喹     
Establishment of a new genus of filovirus (Mengla virus) entry evaluating system and entry inhibitors discovery
CHEN Qing, CHEN Pan-pan, XIN Yi-jing, TANG Ke, ZHANG Xiao-yu, GUO Ying
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Mengla virus (MLAV), isolated from the bats in China, was identified as a new genus of filovirus in 2019, i.e. Dianlovirus genus of Filoviridae family. Among filoviruses, Ebola virus (EBOV) and Marburg virus (MARV) are the most contagious viruses with mortality rates of 24%-90%. Phylogenetic analysis showed that MLAV was closely related to MARV among the members of filovirus family. MLAV enters into host cells via viral glycoprotein (GP). The recombinant virus study indicated that MLAV has a potential for bat-to-human cross-species transmission. In this study, a GP-mediated MLAV entry evaluating model was established, and by using this model, we investigated the susceptibility of MLAV to the human cell lines sourced from different tissues and the African green monkey kidney cell lines. Four compounds, chloroquine, tetrandrine, clomiphene, and toremifene, which were known as EBOV and MARV entry blockers, were tested for HIV/MLAV-GP infection. It was found that chloroquine effectively blocked the entry of MLAV with the half maximal effective concentration (EC50) of 1.56 μmol·L-1, resembling its anti-EBOV and -MARV activities. To the best of our acknowledge, there is no anti-MLAV drug reported by far, and the identification of chloroquine as an MLAV entry inhibitor may provide an insight for developing anti-filovirus agents.
Key words:    Mengla virus    filovirus    entry    chloroquine   
收稿日期: 2019-05-28
DOI: 10.16438/j.0513-4870.2019-0420
基金项目: 国家自然科学基金资助项目(81202568,81473256,81273561);天然药物活性物质与功能国家重点实验室开放课题资助项目(GTZK201907);国家“重大新药创制”专项(2015ZX09102-023,2018ZX09711001-003-002);北京市科委全市成果转化统筹基金(Z151100000115008);新药作用机制研究与药效评价北京市重点实验室资助项目(BZ0150).
通讯作者: 郭颖,Tel:86-10-63161716,E-mail:yingguo6@imm.ac.cn
Email: yingguo6@imm.ac.cn
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