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Journal of Virology, July 2005, p. 8698-8706, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8698-8706.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo

Departments of Medicine,¹ Molecular Microbiology,² Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,³ Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19105,⁴ Apath, LLC, St. Louis, Missouri 63141⁵

Received 10 January 2005/ Accepted 14 April 2005

Previous studies have suggested that -glucosidase inhibitors such as castanospermine and deoxynojirimycin inhibit dengue virus type 1 infection by disrupting the folding of the structural proteins prM and E, a step crucial to viral secretion. We extend these studies by evaluating the inhibitory activity of castanospermine against a panel of clinically important flaviviruses including all four serotypes of dengue virus, yellow fever virus, and West Nile virus. Using in vitro assays we demonstrated that infections by all serotypes of dengue virus were inhibited by castanospermine. In contrast, yellow fever virus and West Nile virus were partially and almost completely resistant to the effects of the drug, respectively. Castanospermine inhibited dengue virus infection at the level of secretion and infectivity of viral particles. Importantly, castanospermine prevented mortality in a mouse model of dengue virus infection, with doses of 10, 50, and 250 mg/kg of body weight per day being highly effective at promoting survival (P 0.0001). Correspondingly, castanospermine had no adverse or protective effect on West Nile virus mortality in an analogous mouse model. Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.

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