One function of N-linked glycans is to assist in the folding of glycoproteins by mediating interactions of the lectin-like chaperone proteins calnexin and calreticulin with nascent glycoproteins. These interactions can be prevented by inhibitors of the ␣-glucosidases, such as N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-DNJ (NN-DNJ), and this causes some proteins to be misfolded and retained within the endoplasmic reticulum (ER). We have shown previously that the NN-DNJ-induced misfolding of one of the hepatitis B virus (HBV) envelope glycoproteins prevents the formation and secretion of virus in vitro and that this inhibitor alters glycosylation and reduces the viral levels in an animal model of chronic HBV infection. This led us to investigate the effect of glucosidase inhibitors on another ER-budding virus, bovine viral diarrhea virus, a tissue culture surrogate of human hepatitis C virus (HCV). Here we show that in MDBK cells ␣-glucosidase inhibitors prevented the formation and secretion of infectious bovine viral diarrhea virus. Data also are presented showing that NN-DNJ, compared with NB-DNJ, exhibits a prolonged retention in liver in vivo. Because viral secretion is selectively hypersensitive to glucosidase inhibition relative to the secretion of cellular proteins, the possibility that glucosidase inhibitors could be used as broadbased antiviral hepatitis agents is discussed. A single drug against HBV, HCV, and, possibly, HDV, which together chronically infect more than 400 million people worldwide, would be of great therapeutic value.

Previously we have shown that the imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In studying the mechanism of action of this compound, it was discovered that imino sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although Nnonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained antiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antiviral activity attributable to a function other than an impact on glycoprocessing. Hepatitis B virus (HBV) is the prototypic member of the hepadnaviradae family of viruses, which includes duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. 1 Worldwide, more than 350 million people are chronically infected with HBV and between 15% and 40% of these individuals will die, if left untreated, from serious liver diseases. 2 The major complication is the development of (primary) hepatocellular carcinoma, which causes an estimated 500,000 deaths annually. 3 Currently there is no definitive cure for chronic HBV infection; however, several FDA (United States Food and Drug Administration) approved clinical approaches have shown promise in some individuals. The first, interferon ␣, is an immunomodulator and has shown to be effective in achieving certain serologic milestones in between 7% and 40% of treated patients. 4 However, the need for parenteral administration, the poor long-term response, and the high frequency of adverse side effects makes interferon not ideal. 4 Also, the actual basis of the activity of interferon ␣ against HBV is unclear. The other FDA-approved HBV medicine is a nucleoside analogue, "3TC-lamivudine," now sold as "lamivudine/Epivir HBV." It is effective against human immunodeficiency virus, as well as HBV, and its mechanism of action is well understood: it is a competitive inhibitor of the viral reverse transcriptase. 5 Unlike interferon, it is orally available and effective in reducing viremia in almost all patients. 6 However, constitutive therapy is necessary and, unfortunately, escape mutants that have gained resistance to 3TC-lamivudine occur in 10% to 20% of those treated per year. Sadly, after 3 years of use, almost 70% of those treated were, again, viremic with HBV. 6 Although the pathogenicity of 3TC-lamivudineresistant escape mutants is uncertain, there clearly remains a need for alternatives and complements to interferon and the nucleoside analogues such as 3TC-lamivudine.N-butyl-deoxynojirimycin (N-butyl-DNJ) and N-nonyldeoxynojirimycin (N-nonyl-DNJ) are glucosidase inhibitors that have been shown to be antiviral against HBV in tissue culture and in the woodchuck model of chronic HBV infection. 7-11 The ␣-glucosidases (I and II) mediate the first steps in the glycan-processing pathway and a...