Inhibitors of Nucleic Acid Synthesis - Antiviral Agents

Inhibitors of Nucleic Acid Synthesis

At present, most antiviral agents are nucleoside analogs that are active against virus-specific nucleic acid polymerases or transcriptases and have much less activity against analogous host enzymes. Some of these agents serve as nucleic acid chain terminators af-ter incorporation into nucleic acids.

Idoxuridine and Trifluorothymidine

Idoxuridine (5-iodo-2 -deoxyuridine, IUdR) is a halogenated pyrimidine that blocks nu-cleic acid synthesis by being incorporated into DNA in place of thymidine and producing a nonfunctional molecule (ie, by terminating synthesis of the nucleic acid chain). It is phosphorylated by thymidine kinase to the active compound. Unfortunately, it inhibits both viral and cellular DNA synthesis, and the resulting host toxicity precludes systemic administration in humans. Idoxuridine can be used topically as effective treatment of her-petic infection of the cornea (keratitis). Trifluorothymidine, a related pyrimidine analog, is effective in treating herpetic corneal infections, including those that fail to respond to IUdR. It has largely replaced idoxuridine.

Acyclovir

This antiviral agent differs from the nucleoside guanosine by having an acyclic (hydroxyethoxymethyl) side chain. Acyclovir is unique in that it must be phosphory-lated by thymidine kinase to be active, and this phosphorylation occurs only in cells infected by certain herpesviruses. Therefore, the compound is essentially nontoxic, because it is not phosphorylated or activated in uninfected host cells. Viral thymidine kinase catalyzes the phosphorylation of acyclovir to a monophosphate. From that point, host cell enzymes complete the progression to the diphosphate and finally the triphosphate.

Activity of acyclovir against herpesviruses directly correlates with the capacity of the virus to induce a thymidine kinase. Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the most active thymidine kinase inducers and are the most readily inhibited by acy-clovir. Cytomegalovirus (CMV) induces little or no thymidine kinase and is not inhibited. Varicella-zoster and Epstein-Barr viruses are between these two extremes in terms of both thymidine kinase induction and acyclovir susceptibility.

Acyclovir triphosphate inhibits viral replication by competing with guanosine triphos-phate and inhibiting the function of the virally encoded DNA polymerase. The selectivity and minimal toxicity of acyclovir is aided by its 100-fold or greater affinity for viral DNA polymerase than for cellular DNA polymerase. A second mechanism of viral inhibition results from incorporation of acyclovir triphosphate into the growing viral DNA chain. This causes termination of chain growth, because there is no 3 -hydroxy group on the acyclovir molecule to provide attachment sites for additional nucleotides. Resistant strains of HSV have been recovered from immunocompromised patients, including pa-tients with acquired immunodeficiency syndrome (AIDS), and in most instances, resis-tance results from mutations in the viral thymidine kinase gene, rendering it inactive in phosphorylation. Resistance may also result from mutations in the viral DNA poly-merase. Resistant virus has rarely, if ever, been recovered from immunocompetent pa-tients, even after years of drug exposure.

Pharmacology and Toxicity Acyclovir is available in three forms: topical, oral, and pa-renteral. Topical acyclovir is rarely used. The oral form has low bioavailability (approxi-mately 10%) but achieves concentrations in blood that inhibit HSV and to a lesser extent varicella-zoster virus (VZV). Intravenous acyclovir is used for serious HSV infection (eg, congenital), encephalitis, and VZV infection in immunocompromised patients. Because acyclovir is excreted by the kidney, the dosage must be reduced in patients with renal fail-ure. CNS and renal toxicity have been reported in patients treated with prolonged high in-travenous doses. Acyclovir is remarkably free of bone marrow toxicity, even in patients with hematopoietic disorders.

Treatment and Prophylaxis Acyclovir is effective in the treatment of primary HSV mu-cocutaneous infections or for severe recurrences in immunocompromised patients. The agent is also useful in neonatal infectious herpes encephalitis, and it is also recommended for VZV infection in immunocompromised patients and varicella in older children or adults. Acyclovir is beneficial against herpes zoster in elderly patients or any patient with eye involvement. In patients with frequent severe genital herpes, the oral form is effective in preventing recurrences. Because it does not eliminate the virus from the host, it must be taken daily to be effective. Acyclovir is minimally effective in the treatment of recur-rent genital or labial herpes in otherwise healthy individuals.

Valacyclovir, Famciclovir, and Penciclovir

Valacyclovir is a prodrug of acyclovir that is better absorbed and therefore can be used inlower and less frequent dosage. Once absorbed, it becomes acyclovir. It is currently ap-proved for use in HSV and VZV infections in immunocompetent adult patients. Dosage adjustment is necessary in patients with impaired renal function.

Famciclovir is similar to acyclovir in its structure and requirement for phosphoryla-tion but differs slightly in its mode of action. After absorption, the agent is converted to penciclovir, the active moiety, which is also a competitive inhibitor of a guanosine triphosphate. However, it does not irreversibly terminate DNA replication. Famciclovir is currently approved for treatment of HSV and VZV infections. Penciclovir, itself, is ap-proved for topical treatment of recurrent herpes labialis.

Ganciclovir

Ganciclovir (DHPG), a nucleoside analog of guanosine, differs from acyclovir by a single carboxyl side chain. This structural change confers approximately 50 times more activity against CMV. Acyclovir has low activity against CMV, because it is not well phosphory-lated in CMV-infected cells due to the absence of the gene for thymidine kinase in CMV. However, ganciclovir is active against CMV and does not require thymidine kinase for phosphorylation. Instead, another viral-encoded phosphorylating enzyme (UL97) is pre-sent in CMV-infected cells that is capable of phosphorylating ganciclovir and converting it to the monophosphate. Then cellular enzymes convert it to the active compound, ganci-clovir triphosphate, which inhibits the viral DNA polymerase.

Oral ganciclovir is available but is inferior to the intravenous form. Oral valganciclovir, a prodrug of ganciclovir, has improved bioavailability and is equivalent to the intravenous form. Toxicity frequently limits therapy. Neutropenia, which is usually reversible, may oc-cur early but often develops during later therapy. Discontinuation of therapy is necessary in patients whose neutrophils do not increase during dosage reduction or in response to cy-tokines. Thrombocytopenia (platelet count 20,000/mm3) occurs in approximately 15% of patients.

Clinical Use Administration of ganciclovir is indicated for the treatment of active CMVinfection in immunocompromised patients, but other herpesviruses (particularly HSV-1, HSV-2, and VZV) are also susceptible. Because AIDS patients with severe CMV infec-tion frequently have concurrent illnesses caused by other herpesviruses, treatment with ganciclovir may benefit associated HSV and VZV infections.

Resistance After several months of continuous ganciclovir therapy for treatment ofCMV, between 5 and 10% of AIDS patients excrete resistant strains of CMV. In virtually all isolates, there is a mutation in the phosphorylating gene, and in a lesser number there may also be a mutation in the viral DNA polymerase. The great majority of these strains remains sensitive to foscarnet, which may be used as alternate therapy. If only a UL97 mutation is present, the strains remain susceptible to cidofovir; however, most of the strains with a ganciclovir-induced mutation in DNA polymerase are cross-resistant to cidofovir. Many clinicians tend to assume that when a patient with CMV retinitis has progression of the disease during treatment, viral resistance has developed. Progression of CMV disease during treatment is probably the result of many factors, only one of which is the susceptibility of the CMV strain to the drug. Blood and tissue concentra-tions of ganciclovir, penetration of ganciclovir into the retinal tissue, and the host im-mune response probably play important roles in determining when clinical progression of CMV disease occurs. Ganciclovir resistance is beginning to be noted in transplant re-cipients, especially those requiring prolonged treatment.