A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase

  • Virology. 2024 Jan:589:109939. doi: 10.1016/j.virol.2023.109939.
Lidan Wang  1 ,  Rui Zhou  1 ,  Yitong Liu  1 ,  Saisai Guo  1 ,  Dongrong Yi  1 ,  Jianyuan Zhao  1 ,  Quanjie Li  1 ,  Yongxin Zhang  1 ,  Chen Liang  2 ,  Jing Wang  3 ,  Guangzhi Shan  4 ,  Shan Cen  5
Affiliations
  • 1. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing, 100050, China.
  • 2. Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, H3T 1E2, Canada.
  • 3. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing, 100050, China. Electronic address: [email protected].
  • 4. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing, 100050, China. Electronic address: [email protected].
  • 5. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing, 100050, China. Electronic address: [email protected].
PMID: 37979208 DOI: 10.1016/j.virol.2023.109939
Abstract

Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its Infection causes congenital brain abnormalities and Guillain-Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV Infection. The non-structural protein NS5 of ZIKV has been recognized as a valuable target of antivirals because of its RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) activities essential for viral RNA synthesis. Here, we report a cell-based assay for discovering inhibitors of ZIKV NS5 and found that 5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM. Furthermore, 5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. Therefore, we have developed a cell-based ZIKV NS5 assay which can be deployed to discover ZIKV NS5 inhibitors and demonstrated the potential of 5-Azacytidine for further development as a ZIKV NS5 inhibitor.

Keywords
5-Azacytidine; Antiviral; NS5; Nucleotide analog inhibitor; ZIKV.
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