PRENYLATION INHIBITORS AS ANTIVIRAL AGENTS in .NET

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a practical antiviral therapy. As detailed below, this hypothesis has now been successfully tested rst using the VLP model system, then with complete infectious virions in a cell culture model, and nally most recently in an animal model of HDV infection.
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PRENYLATION INHIBITORS AS ANTIVIRAL AGENTS
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The discovery that the oncogene Ras is farnesylated and that this prenylation enables both Ras localization to the plasma membrane and Ras-mediated tranformation20 has opened up a ourishing eld of research on prenyltransferase inhibitors. For example, BZA-5B was developed as a speci c inhibitor of farnesyltransferase.21 BZA-5B was shown to inhibit prenylation of the oncoprotein H-RasV12 and abrogate its prenylation-mediated transformation of Rat-1 cells.21,22. BZA-5B was thus a logical choice for evaluating the effect of pharmacologically inhibiting prenylation of another farnesylated protein namely, large delta antigen. Treatment of HDV VLP-producing cells with BZA-5B showed a substantial inhibition of VLP formation at 10 mM concentration of drug and a complete inhibition at 50 mM.23 Surprisingly, minimal cytotoxic effects were observed at any of these concentrations. Indeed, cells can be grown for several generations in BZA-5B without signi cant effects.23 These results demonstrated that prenylation inhibitors (PIs) are valid candidates for preventing HDV particle production. It was important to show, however, that the same effect can be exerted by other types of PIs (i.e., the observed antiviral effect was truly a result of farnesyltransferase inhibition and not related to some other feature of BZA-5B) and to extend this strategy to the inhibition of complete, genome-containing, infectious HDV particles. For these purposes a cell culture system that is capable of producing such infectious particles was utilized and treated with FTI-277,24 a farnesyltransferase inhibitor that is structurally very different from BZA-5B. Dose-dependent inhibition of HDV infectious particle formation at micromolar concentrations of FTI-277 was observed25 (Figure 11.2a). Furthermore, similar ef cacies were achieved against another HDV genotype that is associated with particularly severe clinical disease.25
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conjugation with the viral envelope proteins (HBsAg). (b) Synthesis of the isoprenoid farnesyl begins with the conversion of acetyl-CoA through several biochemical reactions to mevalonate. Mevalonate production by the action of HMG-CoA reductase is the committed step in cholesterol and prenyl lipid synthesis. Further processing reactions lead to the formation of the prenyl lipid farnesyl. Farnesyltransferase (FTase) catalyzes the nal step in prenylation of LHDAg by covalently attaching the farnesyl prenyl group to a cysteine residue contained within a speci c amino acid sequence known as the CXXX box motif (where C cysteine and X one of three amino acids at the carboxyl terminus of the protein substrate). Once prenylated, LHDAg can promote the nal stage in the HDV life cycle, namely, particle formation. See text for details.
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In an effort to further translate these results into a practical clinical therapy, the ef cacy of prenylation inhibition-based antiviral therapy was evaluated in an in vivo animal model of HDV. This animal model combines an HBV transgenic mouse model26 with hydrodynamic transfection27 of the HDV genome into the tail vein of the mice. The HBV transgene helps supply a source of HBV HBsAg that is necessary for HDV particle formation, while the genome injection establishes highef ciency HDV replication in the mouse hepatocytes.28 This combination enables the production of infectious HDV particles in the mouse liver and their secretion into the blood. Single daily doses of two different farnesyltransferase inhibitors at 50 mg/kg/day were administered to such mice. These compounds were well tolerated, as there were no differences in measures of toxicity as compared to vehicle control. A dramatic effect on HDV viremia, however, was observed with both inhibitors achieving complete clearance of detectable viremia within one
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PRENYLATION INHIBITORS: DRUGS WITH BROAD-SPECTRUM ANTIVIRAL POTENTIAL
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week29 (Figure 11.2b). These results combined with the recent development of orally administered PIs that are surprisingly well tolerated in human Phase I/II clinical trials have now set the stage for the rst clinical trials of this novel approach to antiviral therapy in a cohort of HDV-infected patients. Moreover, as detailed below, HDV is best considered as just the rst prototype target for this novel approach to antiviral therapy.
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11.5 PRENYLATION INHIBITORS: DRUGS WITH BROAD-SPECTRUM ANTIVIRAL POTENTIAL As might be expected, exploitation of prenylation by viruses does not appear to be a phenomenon restricted only to HDV. For example, a variety of other medically important viruses encode proteins that possess potential prenylation sites (Table 11.1). These viruses represent a diverse group of viruses including double-stranded DNA viruses, single positive-stranded RNA viruses, and single negative-stranded RNA viruses. The potentially prenylated proteins in these viruses have been implicated in a diverse spectrum of functions ranging from viral assembly to viral replication as well as to date unknown functions (see Table 11.1).
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FIGURE 11.2 Prenylation inhibitors block hepatitis D virus (HDV) particle formation (a) The prenylation inhibitor FTI-277 inhibits production of HDV genome-containing particles. Huh7 cells were cotransfected with HDV and hepatitis B virus (HBV) genome-encoding constructs, which results in the formation of infectious HDV particles.41 The cells were maintained in a daily changed medium containing carrier alone (0.2% DMSO and 400 mM DTT) (lanes 2 and 8) or carrier plus FTI-277 at the following concentrations: 0.5 mM (lanes 3 and 9), 1 mM (lanes 4 and 10), 5 mM (lanes 5 and 11), 10 mM (lanes 6 and 12), or 20 mM (lanes 7 and 13). On day 10 after transfection, cells (lanes 1 to 7) and supernatants (lanes 8 to 13) were processed for northern analysis of HDV RNA. Lane 1 corresponds to total RNA extracted from nontransfected cells subjected to carrier-containing medium (left panel). The amount of HDV RNA in the culture medium of cells treated with the indicated amount of FTI-277 was quantitated using a phosphorimager and plotted as percentage of the untreated control (0 mM) (black bars right panel). To assess for nonspeci c effects of the inhibitor, prior to total RNA extraction, XTT assays were performed to monitor cell metabolism (grey bars right panel) and supernatant HBV surface antigen (HBsAg) levels were determined to monitor for general protein expression and secretion (empty bars right panel). [Part (a) reproduced with permission from the Journal Virology.25] (b) In vivo treatment of HDV viremia with the prenylation inhibitor FTI-2153. HBV transgenic mice were hydrodynamically transfected with an HDV genome-encoding construct to establish HDV viremia.29 Following transfection, the mice were treated with carrier alone (solid circles) or carrier plus FTI-2153 (open circles) for the indicated number of days prior to sacri ce. Serum HDV RNA was quantitated by RT PCR and normalized for transfection ef ciency by quantitation of total HDV liver RNA. See text for details. [Part (b) reproduced with permission from Journal of Clinical Investigation.29]
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