Chemical structure of virustatic antimetabolites

because it undergoes bioactivation only in infected cells, where it preferentially inhibits viral DNA synthesis. (1) A virally coded thymidine kinase (specific to H. simplex and varicella-zoster virus) performs the initial phosphorylation step; the remaining two phosphate residues are attached by cellular kinases. (2) The polar phosphate residues render acyclo-vir triphosphate membrane impermeable and cause it to accumulate in infected cells. (3) Acyclovir triphosphate is a preferred substrate of viral DNA polymerase; it inhibits enzyme activity and, following its incorporation into viral DNA, induces strand breakage because it lacks the 3'-OH group of deoxy-ribose that is required for the attachment of additional nucleotides. The high therapeutic value of acyclovir is evident in severe infections with H. simplex viruses (e.g., encephalitis, generalized infection) and varicella-zoster viruses (e.g., severe herpes zoster). In these cases, it can be given by i.v. infusion. Acy-clovir may also be given orally despite its incomplete (15%-30%) enteral absorption. In addition, it has topical uses. Because host DNA synthesis remains unaffected, adverse effects do not include bone marrow depression. Acyclo-vir is eliminated unchanged in urine (ti/2~ 2.5 h).

Valacyclovir, the L-valyl ester of acyclovir, is a prodrug that can be administered orally in herpes zoster infections. Its absorption rate is approx. twice that of acyclovir. During passage through the intestinal wall and liver, the valine residue is cleaved by esterases, generating acyclovir.

Famcyclovir is an antiherpetic pro-drug with good bioavailability when given orally. It is used in genital herpes and herpes zoster. Cleavage of two acetate groups from the "false sugar" and oxidation of the purine ring to guanine yields penciclovir, the active form. The latter differs from acyclovir with respect to its "false sugar" moiety, but mimics it pharmacologically. Bioactivation of penciclovir, like that of acyclovir, involves formation of the triphosphory-

lated antimetabolite via virally induced thymidine kinase.

Ganciclovir (structure on p. 285) is given by infusion in the treatment of severe infections with cytomegaloviruses (also belonging to the herpes group); these do not induce thymidine kinase, phosphorylation being initiated by a different viral enzyme. Ganciclovir is less well tolerated and, not infrequently, produces leukopenia and thrombo-penia.

Foscarnet represents a diphos-phate analogue.

As shown in (A), incorporation of nucleotide into a DNA strand entails cleavage of a diphosphate residue. Fos-carnet (B) inhibits DNA polymerase by interacting with its binding site for the diphosphate group. Indications: systemic therapy of severe cytomegaly infection in AIDS patients; local therapy of herpes simplex infections.

Amantadine (C) specifically affects the replication of influenza A (RNA) viruses, the causative agent of true influenza. These viruses are endocytosed into the cell. Release of viral DNA requires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a channel protein in the viral coat that permits influx of protons; thus, "uncoating" is prevented. Moreover, amantadine inhibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outbreak of symptoms. It also is an antiparkinsonian (p. 188).

Infected cell: herpes simplex or varicella-zoster

Viral thymidine kinase fl

Acyclovir 0 ^

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