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
Affiliations
Sundy N. Y. Yang
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Sarah C. Atkinson
Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Johanna E. Fraser
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Chunxiao Wang
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Belinda Maher
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Noelia Roman
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia
Jade K. Forwood
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia
Kylie M. Wagstaff
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
Natalie A. Borg
Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
David A. Jans
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia
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.
