2. Academic Validation
  3. Nafamostat mesylate as a broad-spectrum candidate for the treatment of flavivirus infections by targeting envelope proteins

Nafamostat mesylate as a broad-spectrum candidate for the treatment of flavivirus infections by targeting envelope proteins

  • Antiviral Res. 2022 Jun;202:105325. doi: 10.1016/j.antiviral.2022.105325.
Yunzheng Yan 1,  Jingjing Yang 2,  Dian Xiao 1,  Jiye Yin 1,  Mengwen Song 3,  Yijie Xu 1,  Lei Zhao 1,  Qingsong Dai 1,  Yuexiang Li 1,  Cui Wang 3,  Zhuang Wang 4,  Xiaofeng Ren 1,  Xiaotong Yang 1,  Jie Ni 1,  Miaomiao Liu 1,  Xiaojia Guo 1,  Wei Li 1,  Xingjuan Chen 4,  Zhiqiang Liu 3,  Ruiyuan Cao 5,  Wu Zhong 6
Affiliations

Affiliations

  • 1 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 2 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China; School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 3 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
  • 4 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China.
  • 5 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. Electronic address: 21cc@163.com.
  • 6 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. Electronic address: zhongwu@bmi.ac.cn.
PMID: 35460703 DOI: 10.1016/j.antiviral.2022.105325
Abstract

Epidemics caused by flaviviruses occur globally; however, no Antiviral drugs treating flaviviruses infections have yet been developed. Nafamostat (NM) is a protease inhibitor approved for pancreatitis and anti-coagulation. The anti-flavivirus potential of NM has yet to be determined. Here, utilizing in vitro and in vivo Infection assays, we present that NM effectively inhibits Zika virus (ZIKV) and Other flaviviruses in vitro. NM inhibited the production of ZIKV viral RNA and proteins originating from Asia and African lineage in human-, mouse- and monkey-derived cell lines and the in vivo anti-ZIKV efficacy of NM was verified. Mode-of-action analysis using time-of-drug-addition assay, infectivity inhibition assay, surface plasmon resonance assay, and molecular docking revealed that NM interacted with viral particles and blocked the early stage of Infection by targeting the domain III of ZIKV envelope protein. Analysing the anti-flavivirus effects of NM-related compounds suggested that the Antiviral effect depended on the unique structure of NM. These findings suggest the potential use of NM as an anti-flavivirus candidate, and a novel drug design approach targeting the Flavivirus envelope protein.

Keywords

Antiviral; Envelope protein; Flavivirus; Nafamostat; Zika virus.

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