title: Antiviral effects of an iminosugar derivative on flavivirus infections.
abstract: Endoplasmic reticulum (ER) alpha-glucosidase inhibitors, which block the trimming step of N-linked glycosylation, have been shown to eliminate the production of several ER-budding viruses. Here we investigated the effects of one such inhibitor, N-nonyl-deoxynojirimycin (NN-DNJ), a 9-carbon alkyl iminosugar derivative, on infection by Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2). In the presence of NN-DNJ, JEV and DEN-2 infections were suppressed in a dose-dependent manner. This inhibitory effect appeared to influence DEN-2 infection more than JEV infection, since lower concentrations of NN-DNJ substantially blocked DEN-2 replication. Secretion of the flaviviral glycoproteins E and NS1 was greatly reduced, and levels of DEN-2 viral RNA replication measured by fluorogenic reverse transcription-PCR were also decreased, by NN-DNJ. Notably, the viral glycoproteins, prM, E, and NS1 were found to associate transiently with the ER chaperone calnexin, and this interaction was affected by NN-DNJ, suggesting a potential role of calnexin in the folding of flaviviral glycoproteins. Additionally, in a mouse model of lethal challenge by JEV infection, oral delivery of NN-DNJ reduced the mortality rate. These findings show that NN-DNJ has an antiviral effect on flavivirus infection, likely through interference with virus replication at the posttranslational modification level, occurring mainly in the ER.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Wu
authors.forename: Chyan-Jang
authors.initials: CJ
authors.lastname: Lee
authors.forename: Ching-Len
authors.initials: CL
authors.lastname: Liao
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D003715:Dengue / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D004664:Encephalitis Virus, Japanese / Q000187:drug effects* / Q000502:physiology; D004672:Encephalitis, Japanese / Q000188:drug therapy* / Q000821:virology; D005260:Female; D065089:Glycoside Hydrolase Inhibitors; D051379:Mice; D008813:Mice, Inbred ICR
chemical_list: D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin