Acyclovir, selective toxicity

AZT) undergo phosphorylation by host cell kinases to form nucleotide analogs that may inhibit viral DNA polymerases (Figure 49-2). Selective toxicity results because viral DNA polymerases are more sensitive to inhibition by these antimetabolites than are mammalian polymerases. Acyclovir is more selectively toxic than the drugs that require phosphorylation only by host cell enzymes. This increased selectivity is partly a result of initial phosphorylation of acyclovir by a viral thymidine kinase that is absent in uninfected cells (Figure 49-2. top). 

Acyclovir 4,19) is undoubtedly the most interesting of the known anti-viral drugs because of its.high therapeutic index. It is, for example, 3000 times more toxic to herpes simplex virus than to mammalian cells. Somewhat like amino-idoxuridine 4,14b), acyclovir is monophosphorylated by a virus-specified thymidine kinase and then converted to the triphosphoryl derivative which injures the virus by competing, against deoxyguanosine triphosphate, for the virus-specified DNA polymerase in the infected cells (Fyfe et al, 1978). This inhibition puts an end to all DNA synthesis in these cells. Its phosphorylation does not take place in healthy cells, which are thereby spared, and this accounts for most of the selectivity. For the rest the DNA polymerase of infected cells is more sensitive to acyclovir triphosphate than is the DNA polymerase of healthy mammalian cells which, in any case, receive very little of this product (Elion, 1980). 

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