Dideoxyiriosine (dd!)

oxazollne phenoxy oxazollne phenoxy

WIN compounds Fig. 16-1 Some antiviral chemotherapeutic agents

WIN compounds Fig. 16-1 Some antiviral chemotherapeutic agents pend on a rather complex interplay of at least three variables: (1) the efficiency of the virus-coded TK (if any) in converting acyclovir to ACG-P; (2) the efficiency of cellular kinases in converting this intermediate to ACG-PPP; and (3) the susceptibility of the viral DNA polymerase to ACG-PPP. The use of acyclovir for treatment of various herpesvirus diseases is discussed in Chapter 20.

Acyclovir (Zovirax) may be delivered orally, by slow intravenous infusion, or topically as an aqueous cream. As anticipated from in vitro studies, the


Herpesvirus thymidine kinase ACYCLOGUANOSINE - P

Cellular kinases ACYCLOGUANOSINE - PPP

Inhibits viral DNA polymerase thus blocks synthesis ol viral DNA

Fig, 16-2 Mechanism of inhibition of herpesvirus replication by acycloguanosine.

drug is essentially nontoxic Acyclovir levels must be carefully monitored in patients with dehydration or renal impairment, as the drug, which is excreted unchanged through the kidneys, is rather insoluble, and crystalluria may occur.

Acyclovir-resistant mutants of H5V can be recovered in vivo and in cell culture. The mutation is usually located in the gene coding for the viral thymidine kinase, but more rarely is seen in the DNA polymerase gene. There are two kinds of TK mutants: (1) those failing to produce appreciable levels of TK and (2) those in which the enzyme is produced but has an altered substrate specificity such that it can no longer satisfactorily phosphorylate acyclovir. The former (TK- mutants), the most common, may contain a mutation, deletion, or insertion leading to premature termination of translation or the production of a nonfunctional enzyme, whereas the latter (TKa mutants) result from a point mutation causing a more subtle alteration in substrate specificity so that the enzyme no longer phosphorylates acyclovir. The TK" mutants, while able to establish latent infection of ganglia, have a reduced ability to reactivate but can still induce severe disease in immunocompromised hosts.

Certain derivatives of acyclovir display greater activity against varicella-zoster and/or herpes simplex virus, in cultured cells and mice. Clinical investigations have begun on a number of such analogs. For example, valaciclovir is better absorbed orally than is acyclovir, and is rapidly converted to acyclovir in vivo. The TK~ mutants resistant to acyclovir often display cross-resistance to related nucleoside analogs.


A derivative of acyclovir, 9-(l,3-dihydroxy-2-propoxy)methyIguanine (DHPG), known as ganciclovir (Fig. 16-1), is the first drug to offer satisfactory therapy for cytomegalovirus (CMV) infections. CMV encodes an enzyme, not yet characterized, which phosphorylates ganciclovir to the monophosphate; further phosphorylation by cellular kinases yields the active triphosphate, which inhibits the viral DNA polymerase. Resistance in some mutants maps to the phosphorylation gene, in others to the DNA polymerase gene.

Ganciclovir has been used principally to treat severe CMV infections such as retinitis, colitis, and pneumonia in AIDS patients and in transplant ? cip-ients. It is not effective by mouth. Given intravenously for some weeks, gan-

ciclovir may produce a temporary remission in a proportion of cases, but unfortunately the condition generally recurs following its withdrawal. The drug is very toxic, severe neutropenia and thrombocytopenia being common side effects, so this compound should be reserved for life-threatening CMV infections in immunocompromised individuals.


A rather different nucleoside analog, l-0-D-ribofuranosyl-l,2,4-triazole-3-carboxamide, known as ribavirin (Fig. 16-1), was first synthesized in 1972. Despite extensive investigation, it has still not been licensed for general use in many countries because of unpersuasive evidence of antiviral activity in humans as well as indications of toxicity. At first sight, the drug would appear to have potential, as it inhibits the growth of a wide spectrum of RNA and DNA viruses in cultured cells and experimental animals, by what appears to be a multipoint mechanism of action. However, this early promise has not been matched by a comparable degree of efficacy in humans. Further, following oral administration at the usual dosage of about 1 gram per day, a substantial minority of recipients develop a reversible anemia with increased reticulocyte numbers and elevated serum bilirubin levels, while immunosuppressive and teratogenic effects have been demonstrated in animals. The fact that ribavirin monophosphate inhibits the cellular enzyme IMP dehydrogenase, decreasing the pool of GTP, as well as inhibiting guanylyltransferase-mediated 5'-capping of mRNA, suggest that it may be acting on cellular pathways that are somewhat more critical to the virus than to the cell.

Oral or intravenous ribavirin has been claimed to reduce mortality from infections with the exotic Lassa and Hantaan viruses. Ribavirin has also found a niche in the treatment of severe respiratory syncytial viral infections in infants when delivered as an aerosol; a nebulizer is required to generate a small-particle aerosol which is then administered via a mask or oxygen tent for 3-6 days. The value of ribavirin aerosol in the management of severe influenza and parainfluenza infections has yet to be established.

Trisodium Phosphonoformate (PFA, Foscarnet)

The search for inhibitors of enzymes that catalyze the transcription or replication of viral DNA or RNA need not be restricted to the nucleoside analogs. For example, trisodium phosphonoformate, known also as phosphonoformic acid (PFA) or foscarnet (Fig. 16-1), inhibits the DNA polymerase of herpesviruses and hepatitis B, as well as the reverse transcriptase of HIV, by blocking the pyrophosphate binding site on the enzyme. Resistance maps to the DNA polymerase gene. Foscarnet in the form a cream has been claimed to accelerate healing of recurrent facial or genital herpes lesions, and given systemically it can halt the progression of cytomegalovirus infections in immunocompromised patients. The drug also displays some activity against hepatitis B and HIV in viz>o.

Although foscarnet displays some selectivity in that it inhibits cellular DNA polymerase a only at higher concentrations than required to inhibit viral DNA polymerase, it accumulates in bone and is too toxic for the kidneys to be advocated for infections that are not life-threatening.

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