Acycloguanosine triphosphate

Note Herpes simplex virus encodes a virus-specific thymidine. kinase, which phosphorylates the nucleoside analog acyclovir (acycloguanosine) to form acycloguanosine monophosphate. After further phosphorylation, the resulting acycloguanosine triphosphate is incorporated by the viral DNA polymerase into viral DNA, causing chain termination in virus-infected cells.]... 

Acyclovir (acycloguanosine. Fig. 5.221) is a novel type of nucleoside analogue which becomes achvated only in herpes-infected host cells by a herpes-specific enzyme, thymidine kinase. This enzyme inihates conversion of acyclovir initially to a monophosphate and then to the antiviral triphosphate which inhibits viral DNA polymerase. The host cell polymerase is not inhibited to the same extent, and the antiviral triphosphate is not produced in uninfected cells. Ganciclovir (Fig. 5.22J) is up to 100... 

An amino-analogue of idoxuridine known as Aid Urd (4-12) may have clinical potential, because of its very unusual biochemistry. This substance (5-iodo-5 -amino-2, 5 -dideoxyuridine) is activated to its cytostatic triphosphate by the kinase of herpes virus, but not by kinases in uninfected human, murine, or simian cells. It inhibited herpes simplex infection with no sign of toxicity to the host. However, when a mammalian cell was infected with herpes virus, the drug was incorporated into the DNA of both host and virus (Chen, Ward, and Prusoff, 1976). This incorporation will not matter, provided that all infected cells die, and the replication of the virus is halted. Acycloguanosine, recently developed, is 3000 times more toxic to herpes simplex virus than to mammalian cells. This substance, 9-(2-hydroxyethoxymethyl)guanine, zovirax , is phosphorylated by virus-specified thymidine kinase and the product is highly lethal to the virus (only). Healthy human cells carry out little of this phosphorylation, and are unharmed by the product, hence the phenomenal selectivity (Elion et aLy 1977) and its clinical usefulness. 

---