Chapter 1 : Antiherpesviral DNA Polymerase Inhibitors

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Acyclovir (ACV), whose mechanism is detailed in this chapter, heralded the second generation of antivirals for herpesviruses and set the standard for the development of antiviral drugs. Two limitations of oral acyclovir have been its limited oral bioavailability (~15%) and short half-life. These limitations require administration of large pills as often as every four hour. Valacyclovir and famciclovir overcome these limitations and would have completely displaced the use of acyclovir except for the expiration of the acyclovir patent resulting in the availability of low-cost generic drug. Both valacyclovir and famciclovir can be used for applications of oral acyclovir. In the herpesviruses considered here, there are six gene products with activities at the replication fork. The viral proteins that have thus far served as the best targets for antiherpesvirus drugs are the viral DNA polymerases that are required for viral DNA replication, which are thus targets for inhibition, and viral kinases. All of the nucleoside analogs discussed in this chapter are converted to analogs of deoxynucleoside triphosphates (dNTPs) that inhibit herpesvirus DNA polymerases. The mechanism of acyclovir action begins with the TK encoded by herpes simplex virus (HSV) or varicella-zoster virus (VZV). An important unanswered question is whether new antiherpesvirus drugs can be developed to combat drug-resistant human infections. Although the number of drug-resistant HSV infections is relatively small, the need for new drugs that are active against acyclovir-resistant viruses and that have good pharmacokinetic and toxicity profiles is substantial for the patients involved.

Citation: Coen D. 2009. Antiherpesviral DNA Polymerase Inhibitors, p 1-18. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch1
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Image of Figure 1.
Figure 1.

Structures of antiviral nucleoside analogs. (A) Antiherpesvirus nucleoside analogs mimic the deoxynucleoside deoxyguanosine, except for cidofovir, which mimics the deoxynucleotide dCMP. The compounds shown here all contain acyclic moieties that mimic deoxyribose. Valacyclovir and famciclovir are prodrugs of acyclovir and penciclovir, respectively. (B) Foscarnet is a pyrophosphate analog that inhibits viral polymerases. It is approved for treatment of HSV and HCMV infections that are resistant to other drugs.

Citation: Coen D. 2009. Antiherpesviral DNA Polymerase Inhibitors, p 1-18. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch1
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Image of Figure 2.
Figure 2.

Herpesvirus replication cycle. (a) Attachment and entry. Virion envelope proteins attach to cellular receptors on the plasma membrane and then initiate fusion of the two membranes. Nucleocapsids containing the viral genome (hexagons) are liberated into the cytoplasm and transported to nuclear pores. Viral DNA is released into the nucleus, where it circularizes. (b) Transcription. The DNA is transcribed by host RNA polymerase II with the aid of virally encoded factors, giving rise to three classes of viral transcripts that are then translated in the cytoplasm into three classes of viral proteins: immediate early, early, and late. Immediate early proteins typically participate in transcription of the viral DNA. (c) DNA replication. Early proteins typically participate in viral DNA replication. (d) Assembly, encapsidation, and nuclear egress. Late proteins typically participate in assembly of capsids into which replicated DNA is encapsidated. The prevailing model is that the resulting nucleocapsids leave the nucleus by budding through the inner nuclear membrane and then through a complex process of de-envelopment and reenvelopment egress from the cell. Adapted from reference with permission.

Citation: Coen D. 2009. Antiherpesviral DNA Polymerase Inhibitors, p 1-18. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch1
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Image of Figure 3.
Figure 3.

Mechanism of action of acyclovir. (A) Acyclovir is selectively phosphorylated by HSV or VZV thymidine kinase to generate acyclovir monophosphate. Host cellular enzymes then sequentially phosphorylate the drug monophosphate to the di-phosphate and triphosphate (pppACV) forms. (B) Acyclovir triphosphate has a three-step mechanism of inhibition of herpesvirus DNA polymerase in vitro: ( ) the drug triphosphate acts as a competitive inhibitor of dGTP (pppdG) binding; ( ) the drug triphosphate acts as a substrate and is incorporated into the growing DNA chain across from deoxycytidine in the template, terminating elongation; and ( ) the polymerase becomes trapped on the acyclovir-terminated DNA chain when the dNTP binds (here shown as pppdC, dCTP, which would be templated by deoxyguanosine). Modified from reference with permission.

Citation: Coen D. 2009. Antiherpesviral DNA Polymerase Inhibitors, p 1-18. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch1
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Table 1.

Open reading frame designations for herpesvirus polymerases and kinases

Citation: Coen D. 2009. Antiherpesviral DNA Polymerase Inhibitors, p 1-18. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch1

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