ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound

Yuhang Zhang; Zhenjiang Zhang; Fan Zhang; Jiwen Zhang; Jun Jiao; Min Hou; Nianchao Qian; Dongming Zhao; Xiaofeng Zheng; Xu Tan

doi:10.1016/j.virs.2023.03.004

June 2023

. doi: 10.1016/j.virs.2023.03.004

Citation: Yuhang Zhang, Zhenjiang Zhang, Fan Zhang, Jiwen Zhang, Jun Jiao, Min Hou, Nianchao Qian, Dongming Zhao, Xiaofeng Zheng, Xu Tan. ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound .VIROLOGICA SINICA, 2023, 38(3) : 459-469. http://dx.doi.org/10.1016/j.virs.2023.03.004

基于ASFV转录报告系统的高通量筛选将臭椿酮鉴定为一种广谱抗病毒化合物

张宇航 ^a ,
张振江 ^b ,
张帆 ^c ,
张继文 ^b ,
焦俊 ^c ,
侯敏 ^c ,
钱年超 ^c ,
赵东明 ^b,, ,
郑晓峰 ^a,, ,
谭旭 ^c,d,,

a. 湖南农业大学动物医学院;
b. 中国农业科学院, 哈尔滨兽医研究所, 兽医生物技术国家重点实验室;
c. 清华大学医学院传染病研究中心, 清华大学药学院, 北京市结构生物学高精尖创新中心, 清华大学-北京大学生命科学联合中心;
d. 合肥综合性国家科学中心大健康研究院

通讯作者： 赵东明, zhaodongming@caas.cn; 郑晓峰, zheng.x@hunau.edu.cn; 谭旭, mosaictan@hotmail.com
收稿日期： 2022-10-25
录用日期： 2023-03-15

摘要

非洲猪瘟（ASF）是一种急性、高度传染性和致命的猪病毒性疾病，正在严重危害全球养猪业。不幸的是，没有可用于ASF防控的权威疫苗和抗病毒药物。非洲猪瘟病毒（ASFV）是ASF的病原体。在ASFV蛋白中，p72是病毒体中最丰富的成分，因此是抗ASFV药物设计的潜在靶标。本研究中，我们构建了一个由p72（p72-Fluc）启动子驱动的荧光素酶报告系统，该系统由共转染的ASFV RNA聚合酶复合物驱动转录。使用该系统，我们筛选了3000多种化合物并获得了三种有效的抗ASFV化合物。我们进一步评估了抗ASFV的效果，并证明在三个候选物中，臭椿酮（AIL）在纳摩尔浓度（IC50=15 nmol/L）下抑制ASFV的复制。我们的体外实验表明AIL的抗病毒作用与其抑制HSP90-p23辅伴侣有关。最后，我们展示了AIL对寨卡病毒（Zika）和乙型肝炎病毒（HBV）的抗病毒活性，进一步证明AIL是一种潜在的广谱抗病毒剂。
- 非洲猪瘟病毒
- , 复制抑制
- , 广谱抗病毒药物
- , 臭椿酮

ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound

Yuhang Zhang ^a ,
Zhenjiang Zhang ^b ,
Fan Zhang ^c ,
Jiwen Zhang ^b ,
Jun Jiao ^c ,
Min Hou ^c ,
Nianchao Qian ^c ,
Dongming Zhao ^b,, ,
Xiaofeng Zheng ^a,, ,
Xu Tan ^c,d,,

a. College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China;
b. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150009, China;
c. Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;
d. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601 China

Corresponding author: Dongming Zhao, zhaodongming@caas.cn Xiaofeng Zheng, zheng.x@hunau.edu.cn Xu Tan, mosaictan@hotmail.com
Received Date: 25 October 2022
Accepted Date: 15 March 2023

Abstract

African swine fever (ASF) is an acute, highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry. Unfortunately, there are no authoritative vaccine and antiviral drug available for ASF control. African swine fever virus (ASFV) is the etiological agent of ASF. Among the ASFV proteins, p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design. Here, we constructed a luciferase reporter system driven by the promoter of p72, which is transcribed by the co-transfected ASFV RNA polymerase complex. Using this system, we screened over 3200 natural product compounds and obtained three potent candidates against ASFV. We further evaluated the anti-ASFV effects and proved that among the three candidates, ailanthone (AIL) inhibits the replication of ASFV at the nanomolar concentration (IC₅₀ = 15 nmol/L). Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone. Finally, we showed the antiviral activity of AIL on Zika virus and hepatitis B virus (HBV), which supports that AIL is a potential broad-spectrum antiviral agent.
- African swine fever virus (ASFV)
- , Replication inhibition
- , Broad-spectrum antiviral drugs
- , Ailanthone (AIL)

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Electronic Supplementary Material

10.1016j.virs.2023.03.004-ESM.docx