Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer

Sundy N. Y. Yang, Sarah C. Atkinson, Johanna E. Fraser, Chunxiao Wang, Belinda Maher, Noelia Roman, Jade K Forwood, Kylie M. Wagstaff, Natalie A. Borg, David A. Jans

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics.
Original languageEnglish
Article number281
Number of pages15
JournalCells
Volume8
Issue number3
DOIs
Publication statusPublished - 24 Mar 2019

Keywords

  • flavivirus
  • nuclear transport inhibitors
  • importins
  • viral infection
  • dengue virus

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