Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections

Muhammad Imran; Luping Zhang; Bohan Zheng; Zikai Zhao; Dengyuan Zhou; Shengfeng Wan; Zheng Chen; Hongyu Duan; Qiuyan Li; Xueqin Liu; Shengbo Cao; Shaoyong Ke; Jing Ye

doi:10.1016/j.virs.2022.01.007

February 2022

Muhammad Imran, Luping Zhang, Bohan Zheng, Zikai Zhao, Dengyuan Zhou, Shengfeng Wan, Zheng Chen, Hongyu Duan, Qiuyan Li, Xueqin Liu, Shengbo Cao, Shaoyong Ke and Jing Ye. Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections[J]. Virologica Sinica, 2022, 37(1): 94-106. doi: 10.1016/j.virs.2022.01.007

Citation: Muhammad Imran, Luping Zhang, Bohan Zheng, Zikai Zhao, Dengyuan Zhou, Shengfeng Wan, Zheng Chen, Hongyu Duan, Qiuyan Li, Xueqin Liu, Shengbo Cao, Shaoyong Ke, Jing Ye. Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections .VIROLOGICA SINICA, 2022, 37(1) : 94-106. http://dx.doi.org/10.1016/j.virs.2022.01.007

筛选用于抗黄病毒感染的新型脱氢表雄酮合成衍生物

Muhammad Imran ^a,b,c,d ,
张路平 ^a,b,c ,
郑博瀚 ^a,b,c ,
赵子恺 ^a,b,c ,
周登元 ^a,b,c ,
万胜锋 ^e ,
陈政 ^f,g ,
段宏裕 ^a,b,c ,
李秋燕 ^a,b,c ,
刘学芹 ^h ,
曹胜波 ^a,b,c ,
柯少勇 ^i,, ,
叶静 ^a,b,c,,

a 华中农业大学农业微生物学国家重点实验室，湖北武汉，430070
b 华中农业大学动物医学院，湖北省预防兽医学重点实验室，湖北武汉，430070
c 华中农业大学生猪健康养殖协同创新中心，湖北武汉，430070
d 费萨拉巴德农业大学兽医学院，巴基斯坦费萨拉巴德，38040
e 河南省肾脏病与免疫学重点实验室肾内科，河南省人民医院，河南郑州，450003
f 江西省动物卫生重点实验室，江西南昌，330045
g 江西农业大学动物科学与技术学院预防兽医教研室，江西南昌，330045
h 华中农业大学水产学院，湖北武汉，430070
i 湖北省农业科学院，国家生物农药工程研究中心，湖北武汉，430070

通讯作者： 柯少勇, shaoyong.ke@nberc.com; 叶静, yej@mail.hzau.edu.cn
收稿日期： 2021-03-15
录用日期： 2021-10-12

摘要

黄病毒是重要的蚊媒传播的病原体，对全球人类和动物健康造成了严重的危害，但目前仍没有有效的针对黄病毒的治疗药物。脱氢表雄酮 (DHEA) 是一种天然存在于人体内的肾上腺衍生类固醇，与预防各种感染有关。在本研究中，对32种DHEA合成衍生物进行了抗黄病毒效果的检测。根据初步筛选，HAAS-AV3026 和 HAAS-AV3027 用于后续实验，这些衍生物对 JEV（IC50= 2.13和1.98 μM）和 ZIKV（IC50= 3.73和3.42 μM）表现出很强的抗病毒活性。机制研究表明，两种衍生物对黄病毒的吸附和入侵过程没有抑制作用，但是在复制阶段显著抑制黄病毒感染。此外，间接免疫荧光检测、蛋白质印迹分析和荧光定量PCR反应揭示了 DHEA 衍生物在抑制病毒感染、蛋白质生成和病毒 RNA 合成方面对 JEV 和 ZIKV 的强效抗病毒活性。综合起来，我们的结果可能为开发针对黄病毒的新抗病毒药物奠定了基础。
- 黄病毒
- , 日本乙型脑炎病毒
- , 寨卡病毒
- , 脱氢表雄酮
- , 抗病毒药物

Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections

Muhammad Imran ^a,b,c,d ,
Luping Zhang ^a,b,c ,
Bohan Zheng ^a,b,c ,
Zikai Zhao ^a,b,c ,
Dengyuan Zhou ^a,b,c ,
Shengfeng Wan ^e ,
Zheng Chen ^f,g ,
Hongyu Duan ^a,b,c ,
Qiuyan Li ^a,b,c ,
Xueqin Liu ^h ,
Shengbo Cao ^a,b,c ,
Shaoyong Ke ^i,, ,
Jing Ye ^a,b,c,,

a State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China
b Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
c The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China
d Department of Pathology, Faculty of Veterinary Science, University of Agriculture, Faisalabad, 38040, Pakistan
e Department of Nephrology, Henan Provincial Key Laboratory of Kidney Diseases and Immunology, Henan Provincial People's Hospital, Zhengzhou, 450003, China
f Key Laboratory for Animal Health of Jiangxi Province, Nanchang, 330045, China
g Department of Preventive Veterinary Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China
h College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China
i National Biopesticide Engineering Research Center, Hubei Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences, Wuhan, 430070, China

Corresponding author: Shaoyong Ke, shaoyong.ke@nberc.com Jing Ye, yej@mail.hzau.edu.cn
Received Date: 15 March 2021
Accepted Date: 12 October 2021

Abstract

Flaviviruses are important arthropod-borne pathogens that represent an immense global health problem. Their unprecedented epidemic rate and unpredictable clinical features underscore an urgent need for antiviral interventions. Dehydroepiandrosterone (DHEA) is a natural occurring adrenal-derived steroid in the human body that has been associated in protection against various infections. In the present study, the plaque assay based primary screening was conducted on 32 synthetic derivatives of DHEA against Japanese encephalitis virus (JEV) to identify potent anti-flaviviral compounds. Based on primary screening, HAAS-AV3026 and HAAS-AV3027 were selected as hits from DHEA derivatives that exhibited strong antiviral activity against JEV (IC₅₀ = 2.13 and 1.98 μmol/L, respectively) and Zika virus (ZIKV) (IC₅₀ = 3.73 and 3.42 μmol/L, respectively). Mechanism study indicates that HAAS-AV3026 and HAAS-AV3027 do not exhibit inhibitory effect on flavivirus binding and entry process, while significantly inhibit flavivirus infection at the replication stage. Moreover, indirect immunofluorescence assay, Western blot analyses, and quantitative reverse transcription-PCR (qRT-PCR) revealed a potent antiviral activity of DHEA derivatives hits against JEV and ZIKV in terms of inhibition of viral infection, protein production, and viral RNA synthesis in Vero cells. Taken together, our results may provide a basis for the development of new antivirals against flaviviruses.
- Flaviviruses
- , Japanese encephalitis virus (JEV)
- , Zika virus (ZIKV)
- , Dehydroepiandrosterone (DHEA)
- , Antivirals

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