Prenylation Inhibition Rationale for Human HDV Infections

Because mouse hepatocytes do not have the natural receptors for HDV infection, in the above mouse model newly produced virions cannot go on to infect additional rounds of hepatocytes, and therefore the effect of FTIs on virus-related liver injury cannot be fully evaluated. In human HDV infections, however, it would be expected that inhibition of crucial steps in the virus life cycle, such as virion assembly and release, would have a major impact on the course of HDV infection and its associated liver disease.

In addition to the above preclinical data in mice, one of the more compelling reasons to pursue FTI therapy for HDV is that precisely the types of drugs needed have already been developed and used in humans, albeit for a completely different purpose. This fortuitous development is because the requirement for prenylation in transformation by the Ras oncogene was found to be dependent on the same farnesyl modification as occurs on L-HDAg (James et al. 1993; Liu et al. 1999: Sun et al. 1995). Thus, the enzymes responsible for this modification have been important targets for anti-cancer drug design. A variety of prenylation inhibitors has been developed and undergone evaluation for clinical use (Rowinsky et al. 1999; Sebti and Hamilton 2000). These efforts include one of the best examples of successful rational drug design, although it turns out that a wide array of chemical entities can have potent inhibitory activity against FTase. Drugs employing both benzo-diazepine and tricyclic scaffolds, as well as compounds isolated from natural product screens have yielded effective FTIs. The most clinically advanced FTIs have been developed into oral formulations and used in several phase I/II and III trials (Mazieres et al. 2004). Interestingly, their mechanism of action may turn out to involve inhibition of other farnesylated proteins beyond Ras. Except for certain hematological malignancies (Jabbour et al. 2004), however, to date the anti-tumor efficacy of FTIs has proved somewhat disappointing for many oncologic indications. This may well reflect the fact that the targeted form of Ras turns out not to play a primary role in many of these cancers, and that the targeted tumors involve a variety of other important factors. Fortunately, these same considerations do not apply for HDV. In addition, the evaluated FTIs have been shown to be potent and effective inhibitors of FTase and their use was found to generally be quite safe with collectively the main reported side effects being reversible, dose-dependent myelosuppres-sion, fatigue, reversible neuro-cortical toxicity, prolongation of QT interval, and mild gastrointestinal toxicity. Moreover, side effects differed among individual FTIs, suggesting that many side effects might be more related to each specific compound rather than a result of their common inhibition of farnesylation.

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