Prenylation Inhibition Effect on Hdv Vlps

To begin to test the hypothesis that prenylation inhibition-based antiviral therapy might be effective against HDV, a cell line which produces HDV VLPs was created (Glenn et al. 1998). This is the simplest model of HDV assembly and relies on the fact that the minimal requirements for particle assembly are the L-HDAg and the small HBV surface antigen (Chang et al. 1991). Next, a candidate inhibitor was identified based on the fact that prenylation of L-HDAg involves the addition of the prenyl lipid farnesyl via a reaction catalyzed by farnesyltransferase. BZA-5B, a farnesyltransferase inhibitor (FTI) originally developed to prevent prenylation of the farnesylated oncogenic form of Ras (James et al. 1994) was chosen for this purpose. BZA-5B could indeed inhibit L-HDAg prenylation, and the drug was shown to specifically inhibit the prenylation-dependent production of HDV VLPs in a dose-dependent manner (Glenn et al. 1998). Beginning at a BZA-5B concentration of 50 ^M, no particles could be detected. Controls for nonspecific inhibition of protein synthesis and secretion showed essentially no effect of BZA-5B.

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