Prenylation inhibition-based antiviral therapy differs from more classical approaches to antiviral treatment, in that it seeks to deprive the virus access to a host function. By this targeting of a host cell enzyme rather than a virus-specific target, such a strategy may actually impose some difficult challenges for a virus attempting to develop resistance. This is because the targeted locus is not under genetic control of the virus. Moreover, because the farnesyl moi ety of L-HDAg may serve more of a specific ligand role (Hoffman et al. 2000), rather than simply being a mediator of transient interactions with membranes, simple substitution of geranylgeranyl under conditions of FTI-mediated inhibition of farnesylation may be insufficient for restoring HDV assembly. Certainly to date, no such mechanism of resistance has been observed.
At first glance, it might be predicted that inhibiting host cell mediated prenylation would cause intolerable side effects. Surprisingly, however, this does not appear to be the case as FTIs are remarkably well tolerated by host cells in vitro (Dalton et al. 1995), and more importantly in human in vivo trials (Sharma et al. 2002). This might reflect that more host cell prenylated proteins are modified by geranylgeranyl rather than farnesyl (Farnsworth et al. 1990), although recent data suggest this may not be the case (Winter-Vann and Casey 2005). Alternatively, because there is a family of prenyltransferase enzymes, 'cross prenylation' by nontargeted prenyltransferases may occur.
It is worth emphasizing that prenylation inhibition-based antiviral therapy has implications for other viruses besides HDV which are found to have similarly prenylated proteins. Indeed a CXXX box motif is present in proteins of numerous other medically important viruses, as well as in agents with a potential for bioterrorism (Elazar and Glenn 2005). The precise role played by prenylation, however, may differ in each case and need not be restricted to mediating assembly as in HDV. For example, the polymerase proteins of hepatitis A virus and foot and mouth disease virus have a conserved CXXX box. Because the replication of these positive single-strand RNA viruses is thought to occur in intimate association with intracellular membranes, prenylation of these proteins may provide a membrane anchoring function for the catalytic subunit of the respective replication complexes. On the other hand, the UL32 gene product of herpes simplex virus (HSV), which is thought to be involved in virus particle formation, also contains a CXXX box (McGeoch et al. 1988). This suggests that HSV can be considered for targeting by prenylation inhibition and indeed HSV sensitivity to FTI-I treatment has been demonstrated. Interestingly, the interpretation of these latter experiments performed in a Ras-transformed cell line infected with HSV-1 was that the virus exploits the host-cell Ras signaling pathway for infection (Farassati et al. 2001). Thus it is possible to consider that, in addition to direct antiviral effects brought about by inhibiting the prenylation of specific viral proteins, antiviral activity may also be observed as the result of prenylation inhibition-mediated perturbation of host cell pathways dependent on host prenylated proteins. Another example of this has been described for hepatitis C virus where it was proposed that the effect of geranylgeranyltransferase type I inhibitor on HCV RNA replication reflects the virus' dependence on the prenylation of a host cell protein (Ye et al. 2003). This dependence of HCV on host cell geranylgeranylation has recently been suggested by others as well (Kapadia and Chisari 2005). Finally, the mechanism of lovastatin antiviral activity against respiratory syncytial virus was suggested to reflect dependence on prenylation of the host protein RhoA (Gower and Graham 2001).
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