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

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23 Citations (Scopus)
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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

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