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Volume 37 Issue 1
February 2022
    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
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    Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections

    • 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

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

        Corresponding author: Shaoyong Ke, shaoyong.ke@nberc.com
        Corresponding author: Jing Ye, yej@mail.hzau.edu.cn
      • 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
      • 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.

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