TREATMENT OF CHRONIC HEPADNAVIRUS INFECTION IN A WOODCHUCK ANIMAL-MODEL WITH AN INHIBITOR OF PROTEIN-FOLDING AND TRAFFICKING

A novel strategy for anti-viral intervention of hepatitis B virus (HBV ) through the disruption of the proper folding(1) and transport(2) of the hepadnavirus glycoproteins is described. Laboratory reared woodchu cks chronically infected with woodchuck hepatitis virus (WHV) were tre ated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experien ced significant dose dependent decreases in enveloped WHV, resulting i n undetectable amounts in some cases. The reduction in viremia correla ted with the levels of hyperglucosylated glycan in the serum of treate d animals. This correlation supports the mechanism of action associate d with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor(1,2). At N-nonyl-DNJ concentrations tha t prevented WHV secretion, the glycosylation of most serum glycoprotei ns appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the co mpound over the treatment period. We provide the first evidence that g lucosidase inhibitors can be used in vivo to alter specific steps in t he N-linked glycosylation pathway and that this inhibition has anti-vi ral effects.