2. Academic Validation
  3. Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors

Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors

  • Int J Antimicrob Agents. 2019 Oct;54(4):502-506. doi: 10.1016/j.ijantimicag.2019.07.010.
Yuan Lin 1,  Hongjuan Zhang 1,  Weibao Song 1,  Shuyi Si 2,  Yanxing Han 3,  Jiandong Jiang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: hanyanxing@imm.ac.cn.
  • 4 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: jiang.jdong@163.com.
PMID: 31310806 DOI: 10.1016/j.ijantimicag.2019.07.010
Abstract

The current outbreak of Zika virus (ZIKV) is the impetus for novel, safe and efficacious anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication and is logically regarded as an attractive drug target. This study used a fluorescence-based polymerase assay to find an anti-infective drug 10-undecenoic acid zinc salt (UA) which could inhibit RdRp activity with a half maximal inhibitory concentration (IC50) of 1.13-1.25 µM. Molecular docking and site-directed mutagenesis analyses identified D535 as the key amino acid in the interaction between RdRp and UA. Importantly, the surface plasmon resonance assay showed that UA had strong direct binding with ZIKV wild-type RdRp and a relatively weak interaction with D535A-RdRp. As a control, the nucleoside inhibitor sofosbuvir triphosphate (PSI-7409) conferred insensitivity to the fluorescence-based RdRp assay and cannot bind directly with RdRp. Moreover, UA showed anti-ZIKV activity comparable to sofosbuvir. All these results indicate that UA is likely to be a promising lead compound against ZIKV, exhibiting a different mechanism than sofosbuvir.

Keywords

Inhibitor; NS5; RNA-dependent RNA polymerase; Zika virus.

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