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

Cite this

@article{5841f3c6a62641f48315570602d2d89e,
title = "Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer",
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.",
keywords = "flavivirus, nuclear transport inhibitors, importins, viral infection, dengue virus",
author = "Yang, {Sundy N. Y.} and Atkinson, {Sarah C.} and Fraser, {Johanna E.} and Chunxiao Wang and Belinda Maher and Noelia Roman and Forwood, {Jade K} and Wagstaff, {Kylie M.} and Borg, {Natalie A.} and Jans, {David A.}",
year = "2019",
month = "3",
day = "24",
doi = "10.3390/cells8030281",
language = "English",
volume = "8",
journal = "Cells",
issn = "2073-4409",
publisher = "MDPI",
number = "3",

}

Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer. / Yang, Sundy N. Y.; Atkinson, Sarah C.; Fraser, Johanna E.; Wang, Chunxiao; Maher, Belinda; Roman, Noelia; Forwood, Jade K; Wagstaff, Kylie M.; Borg, Natalie A.; Jans, David A.

In: Cells, Vol. 8, No. 3, 281, 24.03.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer

AU - Yang, Sundy N. Y.

AU - Atkinson, Sarah C.

AU - Fraser, Johanna E.

AU - Wang, Chunxiao

AU - Maher, Belinda

AU - Roman, Noelia

AU - Forwood, Jade K

AU - Wagstaff, Kylie M.

AU - Borg, Natalie A.

AU - Jans, David A.

PY - 2019/3/24

Y1 - 2019/3/24

N2 - 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.

AB - 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.

KW - flavivirus

KW - nuclear transport inhibitors

KW - importins

KW - viral infection

KW - dengue virus

U2 - 10.3390/cells8030281

DO - 10.3390/cells8030281

M3 - Article

VL - 8

JO - Cells

JF - Cells

SN - 2073-4409

IS - 3

M1 - 281

ER -