An iminosugar with potent inhibition of dengue virus infection in vivo

• Published in: Antiviral research 2013-04, Vol.98 (1), p.35-43
• Main Authors: Perry, Stuart T., Buck, Michael D., Plummer, Emily M., Penmasta, Raju A., Batra, Hitesh, Stavale, Eric J., Warfield, Kelly L., Dwek, Raymond A., Butters, Terry D., Alonzi, Dominic S., Lada, Steven M., King, Kevin, Klose, Brennan, Ramstedt, Urban, Shresta, Sujan
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Arboviroses; Biological and medical sciences; Cytokines; Dengue - drug therapy; Dengue - immunology; Dengue - virology; Dengue fevers; Dengue virus; Dengue Virus - drug effects; Dengue Virus - physiology; Host-targeted antiviral; Human viral diseases; Humans; Imino Sugars - chemistry; Imino Sugars - pharmacology; Iminosugar; Infectious diseases; Medical sciences; Mice; Mice, Inbred Strains; Mouse model of DHF/DSS; Pharmacology. Drug treatments; Structure-Activity Relationship; Tropical viral diseases; Viral diseases; α-Glucosidase
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2013.01.004

► UV-4 provides effective inhibition of dengue virus infection in vivo. ► Treatment with UV-4 in vivo reduces viral titers in key tissues. ► Cytokine levels are reduced in UV-4 treated mice. ► First study to thoroughly characterize the effect of an iminosugar on DENV. The aim of the present study was to evaluate the ability of the iminosugar drug UV-4 to provide in vivo protection from lethal dengue virus (DENV) challenge. This study utilized a well-described model of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)-like lethal disease in AG129 mice lacking the type I and II interferon receptors. Herein, we present UV-4 as a potent iminosugar for controlling DENV infection and disease in this mouse model. Specifically, administration of UV-4 reduced mortality, as well as viremia and viral RNA in key tissues, and cytokine storm. In addition, UV-4 treatment can be delayed, and it does not alter the anti-DENV antibody response. These results have set the foundation for development of UV-4 as a DENV-specific antiviral in phase I human clinical trials.