Inhibitors of Viral DNA Polymerase

Many of the successful antiviral agents described to date are nucleoside analogs, most of which are restricted in their antiviral activity to the herpesviruses. The early prototypes, such as adenine arabinoside, were relatively undis-criminating inhibitors of both cellular and viral DNA synthesis which produced toxic side effects, directed especially at dividing cells in the bone marrow and gastrointestinal tract.

Acycloguanosine (Acyclovir) and Homologs

A major breakthrough in antiviral chemotherapy occurred in 1977 when Elion and colleagues developed a prodrug that depends on a viral enzyme to convert it to form. Acycloguanosine, now commonly known as acyclovir, is a guanine derivative with an acyclic side chain, the full chemical name being 9-(2-hydroxyethoxymethyl)guanine {Fig. 16-1). Its unique advantage over earlier nucleoside derivatives is that the herpesvirus-encoded enzyme, thymidine kinase (TK), which has broader specificity than cellular TK, is required to phosphorylate acycloguanosine intracellularly to acycloguanosine monophosphate (ACG-P); a cellular GMP kinase then completes the phosphorylation to the active agent, acycloguanosine triphosphate (ACG-PPP) (Fig. 16-2). Further, ACG-PPP inhibits the herpesvirus-encoded DNA polymerase at least 10 times more effectively than it does cellular DNA polymerase a. It acts as both inhibitor and substrate of the viral enzyme, competing with GTPand being incorporated into DNA, leading to chain termination because acyclovir lacks the 3'-hydroxyl group required for chain elongation. Since activation of the prodrug needs the viral TK, acyclovir is essentially nontoxic to uninfected cells but is powerfully inhibitory to viral DNA synthesis in infected cells, giving it much greater selectivity than the earlier nucleoside analogs.

Herpes simplex viruses types 1 and 2 (HSV-1 and -2) are both very susceptible to acyclovir; varicella-zoster virus (VZV) is susceptible at somewhat higher concentrations of the drug. Other human herpesviruses, which do not possess a gene coding for TK, are susceptible to acycloguanosine only at much greater doses; this results from limited production of ACG-P by cellular GMP kinase. The relative sensitivity of different herpesviruses seems to de-

Acycloguanosine (Acyclovir)


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