Prenylation Inhibition Effect on Infectious HDV Particles

These results provided the first demonstration that HDV assembly might be susceptible to pharmacologic inhibition. Next this strategy was extended to a system that produces complete, infectious HDV virions containing an intact genome and another farnesyltransferase inhibitor, FTI-277 (Bordier et al. 2002). This system was based on co-transfecting Huh7 cells with plasmids encoding the complete HDV and HBV genomes (Sureau et al. 1992). Mid-nanomolar concentrations of FTI-277 dramatically inhibited virion production, and low micromolar drug concentrations decreased virion production to below the limit of detection (Bordier et al. 2002). Again, there was no significant effect on general protein synthesis and secretion or cell metabolism. Because the molecular structures of BZA-5B and FTI-277 are very different, these results strongly suggested that their mechanism of action against HDV was indeed a reflection of their common FTI activity rather than some other feature of the inhibiting drugs. Thus even with the added complexity and assembly determinants of infectious HDV virions compared to VLPs, the former are also sensitive to pharmacological inhibition of prenylation. Moreover, using a similar virion production model, it was demonstrated that HDV genotype III virions-which are associated with particularly severe clinical disease (Casey et al. 1993)-are as sensitive to prenylation inhibition as were HDV genotype I virions (Bordier et al. 2002).

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