Repurposing of the antihistamine mebhydrolin napadisylate for treatment of Zika virus infection

Bioorg Chem. 2022 Nov:128:106024. doi: 10.1016/j.bioorg.2022.106024. Epub 2022 Jul 22.

Abstract

Zika virus (ZIKV) infection can lead to severe neurological disorders and fetal defects, which has become a public health problem worldwide. However, effective clinical treatment for ZIKV infection was still arduous. Antihistamines are attractive candidates for drug repurposing due to their low price and widespread availability. Here we screened FDA-approved antihistamine drugs to obtain anti-ZIKV candidate compounds and identified mebhydrolin napadisylate (MHL) that exhibits the potent inhibition of ZIKV infection in various cell lines in a histamine H1 receptor-independent manner. Mechanistic studies suggest that MHL acts as a ZIKV NS5 RNA-dependent RNA polymerase (RdRp) inhibitor, supported by a structure-activity relationship (SAR) analysis showing the correlation between the inhibitory effect upon viral RNA synthesis and ZIKV infectivity. Furthermore, MHL was shown to bind ZIKV NS5 RdRp in vitro and predicted to interact with key residues at the active site of ZIKV NS5 RdRp by molecular docking analysis. Our data together suggest that MHL suppresses ZIKV infection through the inhibition of ZIKV NS5 RdRp activity. This study highlights that MHL might be a promising clinical anti-ZIKV therapeutic.

Keywords: Anti-virus; Antihistamine drugs; Antiviral agents; RNA-dependent RNA polymerase; Zika Virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Carbolines
  • Drug Repositioning
  • Histamine Antagonists / metabolism
  • Histamine Antagonists / pharmacology
  • Histamine Antagonists / therapeutic use
  • Humans
  • Molecular Docking Simulation
  • RNA-Dependent RNA Polymerase
  • Zika Virus Infection* / drug therapy
  • Zika Virus*

Substances

  • Antiviral Agents
  • Carbolines
  • Histamine Antagonists
  • RNA-Dependent RNA Polymerase
  • diazoline