High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses
Sundy N. Y. Yang,
Belinda Maher,
Chunxiao Wang,
Kylie M. Wagstaff,
Johanna E. Fraser,
David A. Jans
Affiliations
Sundy N. Y. Yang
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
Belinda Maher
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
Chunxiao Wang
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
Kylie M. Wagstaff
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
Johanna E. Fraser
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
David A. Jans
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia
Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective therapeutic currently available and controversy surrounding the one approved vaccine. A key factor in dengue viral replication is the interaction between DENV nonstructural proteins (NS) 5 and 3 (NS3) in the infected cell. Here, we perform a proof-of-principle high-throughput screen to identify compounds targeting the NS5-NS3 binding interface. We use a range of approaches to show for the first time that two small molecules–repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)–inhibit NS5-NS3 binding at low μM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low μM concentrations against not only DENV-2, but also Zika virus (ZIKV) and West Nile virus (WNV). This work highlights the NS5-NS3 binding interface as a viable target for the development of anti-flaviviral therapeutics.
