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Journal of Virology, April 2002, p. 3596-3604, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3596-3604.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections

Shu-Fen Wu,1,2 Chyan-Jang Lee,1,2 Ching-Len Liao,1,3 Raymond A. Dwek,4 Nicole Zitzmann,4 and Yi-Ling Lin1,2*

Graduate Institute of Life Sciences,1 Department of Microbiology and Immunology, National Defense Medical Center,3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China,2 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom4

Received 21 September 2001/ Accepted 9 January 2002

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.

* Corresponding author. Mailing address: Institute of Biomedical Sciences, Academia Sinica, No. 128, Sec. 2, Academic Road, Nankang, Taipei 11529, Taiwan, Republic of China. Phone: (886) 2-2652-3902. Fax: (886) 2-2785-8847. E-mail: yll{at}ibms.sinica.edu.tw.

Journal of Virology, April 2002, p. 3596-3604, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3596-3604.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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