Inhibition of Hepatitis B Virus Dna Replication by Imino Sugars Without the Inhibition of the Dna Polymerase: Therapeutic Implications

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Abstract
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 N–nonyl–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. This hypothesis was confirmed by experiments showing that N–nonyl–deoxygalactojirimycin (N–nonyl–DGJ), an alkyl derivative of galactose with no impact on glycoprocessing, retains anti–HBV activity. The data suggest that N–nonyl–DGJ exerts its antiviral action at a point before viral envelopment and may prevent the proper encapsidation of the HBV pregenomic RNA.

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