Nucleic Acid Synthesis

Many of the most effective antiviral drugs exploit the error-prone virally encoded enzymes used to replicate viral nucleic acid. With few exceptions, however, the use of these drugs is generally limited to treating infections caused by the herpesviruses and HIV.

Nucleoside Analogs

A growing number of antiviral drugs are nucleoside analogs, compounds similar in structure to a nucleoside. These analogs can be phosphorylated in vivo by a virally encoded or normal cellular enzyme to form a nucleotide analog, a chemical structurally similar to the nucleotides of DNA and RNA. In some cases, incorporation of the nucleotide analog results in termination of the growing nucleotide chain, in a manner analogous to the in vitro technique used to determine the sequence of DNA. In other cases, incorporation of the analog results in a defective strand with altered base-pairing properties. ■ nucleotide, p. 31 ■ DNA sequencing, pp. 229,237

The basis for the selective toxicity of most nucleoside analogs is the fact that virally encoded enzymes are much more prone to incorporating the corresponding nucleotide analogs than are host polymerases. Thus, more damage is done to the rapidly replicating viral genome than to host cells. Nucleoside analogs, however, are only effective against replicating viruses. Because viruses such as herpesvirus and HIV can remain latent in cells, the drugs do not cure these infections; they simply limit the duration of the active infection. The virus can still undergo reactivation, causing a reoccurrence of symptoms.

Most nucleoside analogs are reserved for severe infections because of their significant side effects. An important exception to this principle is acyclovir, a drug used to limit herpesvirus infections. This drug causes little harm to uninfected cells because the conversion of acyclovir to a nucleotide analog does not utilize a normal cellular enzyme but instead requires a virally encoded enzyme. The enzyme is only present in cells infected by herpesviruses such as herpes simplex virus (HSV) and varicella-zoster virus (VZV). Thus, acyclovir does not get converted to a nucleotide analog in uninfected cells. Other nucleoside analogs include ganciclovir, which is used to treat life-threatening or sight-threatening cytomegalovirus (CMV) infections in immuno-compromised patients, and ribavirin, which is used to treat respiratory syncytial virus infections (RSV) in newborns. ■ herpes simplex virus, pp. 606, 653 ■ varicella zoster, p. 548

A number of different nucleoside analogs are used to treat HIV infection by interfering with the activity of reverse tran-scriptase. Unfortunately, the virus rapidly develops mutational resistance against these drugs, which is why they are often used in combination with other anti-HIV drugs. Nucleoside analogs that interfere with reverse transcription include zidovudine (AZT), didanosine (ddI), and lamivudine (3TC). Two of these are often used in combination for HIV therapy.

Non-Nucleoside Polymerase Inhibitors

Non-nucleoside polymerase inhibitors are compounds that inhibit the activity of viral polymerases by binding to a site other than the nucleotide-binding site. One example, foscarnet, is used to treat infections caused by ganciclovir-resistant CMV and acy-clovir-resistant HSV.

Chapter 21 Antimicrobial Medications

Table 21.3 Characteristics of Antiviral Drugs

Target/Drug Examples

Comments/Characteristics

Viral Uncoating

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