title: Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin.
abstract: Infection by one of the 4 distinct serotypes of dengue virus (DENV) threatens >40% of the world's population, with no efficacious vaccine or antiviral agent currently available. DENV replication through the virus-encoded nonstructural protein (NS) 5 protein occurs in the infected cell cytoplasm, but NS5 from DENV2 has thus far been shown to localize strongly in the nucleus throughout infection. Here we use specific antibodies cross-reactive with NS5 from DENV1-4 to demonstrate nuclear localization of NS5 from all DENV serotypes for the first time in both infected as well as transfected cells, although to differing extents. The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/β in vitro, and protected against infection from DENV1-4. Ivermectin thus has potential in the clinical setting as a dengue antiviral.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: M Y F
authors.initials: MY
authors.lastname: Tay
authors.forename: J E
authors.initials: JE
authors.lastname: Fraser
authors.forename: W K K
authors.initials: WK
authors.lastname: Chan
authors.forename: N J
authors.initials: NJ
authors.lastname: Moreland
authors.forename: A P
authors.initials: AP
authors.lastname: Rathore
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: S G
authors.initials: SG
authors.lastname: Vasudevan
authors.forename: D A
authors.initials: DA
authors.lastname: Jans
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000821:virology*; D003593:Cytoplasm / Q000821:virology; D003715:Dengue / Q000188:drug therapy / Q000821:virology*; D003716:Dengue Virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C582223:NS5 protein, dengue virus; D017361:Viral Nonstructural Proteins; D007559:Ivermectin
keywords: Dengue; Dengue virus; Flavivirus; Ivermectin; Nonstructural protein-5; Nuclear import