Structure-Activity Relationship of a New Class of Anti-Hepatitis B Virus Agents

Abstract

N-Nonyl-deoxy-galactonojirimycin (N-nonyl-DGJ) has been shown to reduce the amount of hepatitis B virus (HBV) produced by tissue cultures under conditions where cell viability is not affected. We show here that the compound N-nonyl-DGJ was effective against lamivudine-resistant HBV mutants bearing the YMDD motif in the polymerase gene, consistent with the compound's activity being distinct from those of nucleoside inhibitors. To better understand the chemical structures that influence its antiviral activity, a series of imino sugar derivatives were made and tested for their antiviral activity against HBV. This work suggests that the antiviral activity of the alkovirs requires an alkyl chain length of at least eight carbons but that the galactose-based head group can be modified with little or no loss in activity.

α-Galactosylceramide and Novel Synthetic Glycolipids Directly Induce the Innate Host Defense Pathway and Have Direct Activity against Hepatitis B and C Viruses

“…Structure activity relationship analysis led to the development of an analogue of NN-DGJ, N-9-oxadecyl-6-methyl-DGJ, which was as potent and efficacious as the parent molecule but with a much improved toxicity profile. Similar to the structural requirements for ␣-galactosylceramide, structural analysis of the synthetic glycolipids also highlighted the importance of a galactose head group in the antiviral activity of these compounds (16). Synthetic glycolipids with alternative head groups, such as mannose or fucose, have reduced potency compared to those with the galactose head group (16).…”

“…Previous work showed that the synthetic glycolipid N-nonyldeoxy-galactonojirimycin (NN-DGJ) could inhibit the production and secretion of HBV in vitro (16,17). The exact molecular mechanism whereby NN-DGJ (and the chemical family it represents) induced its antiviral effect is not fully known but is analogous to the effect of inducers of the innate host defense pathway against HBV (8,24).…”

“…However, the direct activity of this compound against HBV was not tested and remained a possibility. Thus, the direct antiviral activities of ␣-galactosylceramide and our smaller orally available glycolipids were tested in tissue culture using the stable HBV-producing cell line HepG2 2.2.15 (16,17,22,23). The results, shown in Fig.…”

“…Recent work has shown that the mechanism of action of these compounds is similar to that of alpha interferon (8) in that they either inhibit the formation of pregenomic RNA-containing capsids or accelerate their degradation (15). Further work characterizing the structural requirements for antiviral activity highlighted a need for both a sugar head group and an unbroken alkyl tail of at least eight carbons (16). Structure activity relationship analysis led to the development of an analogue of NN-DGJ, N-9-oxadecyl-6-methyl-DGJ, which was as potent and efficacious as the parent molecule but with a much improved toxicity profile.…”

“…This is a galactose analogue in which the ring oxygen has been replaced with a nitrogen atom and the anomeric hydroxyl group of galactose is absent. N-7-oxanonyl-6-methyl-DGJ has been shown to have no activity against HBV (16). Prior structure-activity relationship analysis has indicated that an unbroken alkyl chain length of Ͼ8 is required for antiviral activity (16).…”