An iminosugar with potent inhibition of dengue virus infection in vivo Stuart T. Perry a,1 , Michael D. Buck a,1 , Emily M. Plummer a,1 , Raju A. Penmasta b , Hitesh Batra b , Eric J. Stavale c , Kelly L. Warfield c , Raymond A. Dwek d , Terry D. Butters d , Dominic S. Alonzi d , Steven M. Lada a , Kevin King a , Brennan Klose e , Urban Ramstedt e , Sujan Shresta a,⇑ a La Jolla Institute for Allergy & Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA b United Therapeutics, 1040 Spring Street, Silver Spring, MD 20910, USA c Integrated Biotherapeutics, Inc., 21 Firstfield Road, Suite 100, Gaithersburg, MD 20878, USA d Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, Oxford, UK e Unither Virology, 1040 Spring Street, Silver Spring, MD 20910, USA article info Article history: Received 3 December 2012 Revised 16 January 2013 Accepted 22 January 2013 Available online 31 January 2013 Keywords: Dengue virus Iminosugar a-Glucosidase Host-targeted antiviral Mouse model of DHF/DSS abstract 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 den- gue 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 devel- opment of UV-4 as a DENV-specific antiviral in phase I human clinical trials. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction With rapid increase in geographic spread and lack of vector con- trol, dengue virus (DENV) has re-emerged as an important infec- tious disease pathogen. Transmitted by Aedes aegypti and Aedes albopictus mosquitoes, the virus causes a wide variety of symptoms in people in a complicated interplay with the host immune system (Halstead, 2007). Clinical disease ranges from dengue fever (DF), an acute, self-limiting febrile illness, to the more severe and life- threatening dengue hemorrhagic fever and shock syndrome (DHF/DSS) (Halstead, 2007). Despite an annual number of infec- tions approaching 50 million worldwide and a rise in disease severity, no vaccines or antiviral therapies are currently available (Coller et al., 2010; Gubler, 1998; Julander et al., 2011). Although vaccines have been successfully created against other flaviviruses, such as yellow fever virus (YFV) and Japanese enceph- alitis virus (JEV), an incomplete understanding of dengue immuno- pathogenesis has impeded the development of a safe and effective vaccine or antiviral. DENV exists as four antigenically distinct ser- otypes (DENV1-4), each containing multiple genotypes that cause infection in humans (Gubler, 1998). Epidemiological studies of dengue endemic areas have revealed an increased risk for severe disease during a secondary infection. One of the proposed mecha- nisms of this phenomenon is known as antibody-dependent enhancement (ADE) of disease. In brief, cross-reactive, non-neu- tralizing antibodies generated during a primary infection by one DENV serotype or acquired passively at birth, contribute to the development of severe disease upon infection by one of the other three serotypes (Balsitis et al., 2010; Zellweger et al., 2010). An- other leading theory, T cell original antigenic sin, involves cross- reactive T cells from the original infecting serotype contributing to the immunopathogenesis of a secondary heterologous infection due to their low-affinity (Rothman, 2011). In light of these theories, a DENV vaccine that induces robust, long-term protection across all serotypes and a therapeutic that has broad-spectrum antiviral activity would be most effective. An antiviral that targets a common host pathway could provide an advantage to the issues faced by therapies targeting viral enzymes or mechanisms, such as viral heterogeneity and the 0166-3542/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.antiviral.2013.01.004 Abbreviations: DENV, dengue virus; DF, dengue fever; DHF/DSS, dengue hemorrhagic fever/dengue shock syndrome; YFV, yellow fever virus; JEV, Japanese encephalitis virus; ADE, antibody dependent enhancement; ER, endoplasmic reticulum; DNJ, deoxynojirimycin; NGC, New Guinea C; GE, genomic equivalents; PFU, plaque forming units; PrM, pre-membrane; E, envelope; LD 90 , 90% lethal dose. ⇑ Corresponding author. Address: La Jolla Institute for Allergy & Immunology, Center for Infectious Disease, Division of Vaccine Discovery, 9420 Athena Circle, La Jolla, CA 92037, USA. Tel.: +1 858 752 6944; fax: +1 858 752 6987. E-mail address: sujan@liai.org (S. Shresta). 1 These authors contributed equally to this work. Antiviral Research 98 (2013) 35–43 Contents lists available at SciVerse ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral