{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T11:09:34Z","timestamp":1783508974454,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Dengue virus (DENV) threatens almost 70% of the world\u2019s 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\u2013repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)\u2013inhibit NS5-NS3 binding at low \u03bcM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low \u03bcM 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.<\/jats:p>","DOI":"10.3390\/cells11040730","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:14:46Z","timestamp":1645431286000},"page":"730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses"],"prefix":"10.3390","volume":"11","author":[{"given":"Sundy N. Y.","family":"Yang","sequence":"first","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8900-6876","authenticated-orcid":false,"given":"Belinda","family":"Maher","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-2467","authenticated-orcid":false,"given":"Chunxiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie M.","family":"Wagstaff","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna E.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-4745","authenticated-orcid":false,"given":"David A.","family":"Jans","sequence":"additional","affiliation":[{"name":"Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Monash, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S0188-4409(02)00378-8","article-title":"The global emergence\/resurgence of arboviral diseases as public health problems","volume":"33","author":"Gubler","year":"2002","journal-title":"Arch. 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