Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo.
Previous studies have suggested that alpha-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 < or = 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.
Whitby
Kevin
K
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, MO 63110, USA.
Pierson
Theodore C
TC
Geiss
Brian
B
Lane
Kelly
K
Engle
Michael
M
Zhou
Yi
Y
Doms
Robert W
RW
Diamond
Michael S
MS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000187:drug effects*; D007212:Indolizines / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012367:RNA, Viral / Q000096:biosynthesis; D014771:Virion / Q000187:drug effects; D014901:West Nile Fever / Q000188:drug therapy; D014902:West Nile virus / Q000187:drug effects; D015005:Yellow fever virus / Q000187:drug effects; D054836:Indolizidines
D000998:Antiviral Agents; D007212:Indolizines; D012367:RNA, Viral; C037806:castanospermine; D054836:Indolizidines