Viral DNA synthesis

The answer is b. (Hardman, p 1203.) Trifluridine inhibits viral activity in HSV types 1 and 2, CMV, vaccinia, and perhaps adenovirus. It acts as a viral DNA synthesis inhibitor by irreversibly blocking thymidylate synthetase. Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate accumulation into DNA It is used in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV 1 and 2. 

AZT is phosphorylated by cellular enzymes to the triphosphate, which competes with normal substrates for formation of DNA by reverse transcriptase, and blocks viral DNA synthesis. Mammalian DNA polymerase is relatively unaffected, but there can be some toxic effects. AZT is used in AIDS treatment along with other antiretroviral drugs. 

Mechanism of Action An anti-infective that inhibits viral DNA synthesis by incorporating itself into the growing viral DNA chain. Therapeutic Effect Suppresses replication of cytomegalovirus (CMV). 

Mechanism of Action A guanosine nucleoside analog that inhibits hepatitis B viral polymerase, which blocks reverse transcriptase activity. Therapeutic Effect Interferes with viral DNA synthesis. 

Mechanism of Action Penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Therapeutic Effect An antiviral compound that has inhibitory activity against herpes simplex virus types 1 (HSV-1)... 

Mechanism of Action A nucleoside reverse transcriptase inhibitor that inhibits viral DNA synthesis. Therapeutic Effect Prevents replication of HIV-1. 

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by host cell enzymes (Figure 49-3). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates—only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms competition with deoxyGTP for the viral... 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

Inhibits HSV-2 polymerase competitively with deoxyguanosine triphosphate, selectively inhibiting herpes viral DNA synthesis and replication... 

Mechanism of Action Inhibits replication by interfering with viral DNA synthesis CMV retinitis in immunocompromised patients... 

Mechanism of Action. This drug impairs viral DNA synthesis by inhibiting the enzymes that incorporate a specific nucleotide (thymidine) into viral DNA. The drug also substitutes itself for thymidine in the viral DNA sequence, thus creating a false DNA code that is ineffective in promoting viral replication. 

Research in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. 

Other notable research by Elion led to the development of the antiviral drug Acyclovir (acycloguanosine), which has been used to treat the herpes simplex viruses. Her studies during the 1970s showed that Acyclovir inhibited viral replication by interfering with viral DNA synthesis. The sub-... 

Liu HS, Bilimoria SL (1990), Infected cell specific protein and viral DNA synthesis in productive and abortive infections of Spodoptera frugiperda nuclear polyhedrosis virus, Arch Virol. 115 101-113. 

Fig. 14.1. Time course of SV40 infection. Monkey cells in monolayer culture, infected with SV40 at 1-10 p.f.u. per cell. T antigen may be detected by immunofluorescence, viral DNA synthesis by labelling with [yH]thymidine followed by separation of viral DNA (by Hirt extraction, SDS gradient centrifugation or agarose gel electrophoresis) and mature virions by infectivity using a plaque assay. (Data from Tooze, 1973 Girard et al., 1975 and Basilico and Zouzias, 1976.)...

Herpesviruses are associated with a broad spectrum of diseases, e.g., cold sores, viral encephalitis, and genital infections, the latter being a hazard to the newborn during parturition. The drugs that are effective against these viruses exert their actions during the acute phase of viral infections and are without effect in the latent phase. Except for foscar-net, all are purine or pyrimidine analogs that inhibit viral DNA synthesis. 

Vidarabine [vye DARE a been] arabinofuranosyl adenine, ara-A, adenine arabinoside) is one of the most effective of the nucleoside analogs and is also the least toxic. However, it has been supplanted clinically by acyclovir, which is more efficacious and safe. Although vidarabine is active against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), its use is limited to treatment of immunocompromised patients with herpes simplex keratitis or encephalitis, or VZV infections. Vidarabine, an adenosine analog, is converted in the cell to its 5 -triphosphate analog (ara-ATP), which is postulated to inhibit viral DNA synthesis. Some resistant herpes virus... 

Aciclovir is an analogue of the nucleic acid guanosine and interrupts viral DNA synthesis by inhibiting viral DNA polymerase. 

Famciclovir, an oral prodrug of penciclovir, is well absorbed orally and is rapidly converted to active penciclovir with a bioavailability of 65% to 77%. Penciclovir is active against HSV-1, HSV-2, and VZV with potency and spectrum of activity similar to acyclovir, in that penciclovir selectively affects viral DNA synthesis and inhibits replication. The plasma half-life of the active drug, penciclovir phosphate, is very long, which permits infrequent dosing. 

Acyclovir selectively inhibits viral DNA synthesis. It is preferentially activated in virally infected cells. Cellular uptake and initial phosphorylation are facilitated by the herpes virus thymidine kinase. The affinity of acyclovir for HSV... 

Adclovir inhibits viral DNA synthesis only after phosphorylation by virus-specific thymidine kinase, which accounts for its high therapeutic index. 

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