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.