Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin

• Published in: Antiviral research 2013-09, Vol.99 (3), p.301-306
• Main Authors: Tay, M.Y.F., Fraser, J.E., Chan, W.K.K., Moreland, N.J., Rathore, A.P., Wang, C., Vasudevan, S.G., Jans, D.A.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Arboviroses; Biological and medical sciences; Cell Nucleus - virology; Cytoplasm - virology; Dengue; Dengue - drug therapy; Dengue - virology; Dengue fevers; Dengue virus; Dengue Virus - classification; Dengue Virus - drug effects; Dengue Virus - genetics; Dengue Virus - metabolism; Flavivirus; Human viral diseases; Humans; Infectious diseases; Ivermectin; Ivermectin - pharmacology; Medical sciences; Nonstructural protein-5; Nuclear import; Pharmacology. Drug treatments; Protein Transport - drug effects; Tropical viral diseases; Viral diseases; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2013.06.002

•NS5 from all 4 DENV serotypes traffics to the nucleus, but to differing degrees.•DENV1 and 2 NS5 bind nuclear import proteins with similar affinity.•Nuclear import inhibitor, Ivermectin, blocks DENV1–4 replication. 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.