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Chapter 58: Antiviral Agents (Nonretroviral)

INTRODUCTION

Viruses are simple microorganisms that consist of either double- or single-stranded DNA or RNA enclosed in a protein coat called a capsid. Some viruses also possess a lipid envelope derived from the infected host cell, which, like the capsid, may contain antigenic glycoproteins. Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell–directed nucleic acid or protein synthesis (Table 58-1). Host cell molecules that are essential to viral replication also offer targets for intervention. Figure 58-1 gives a schematic diagram of the replicative cycle of typical DNA and RNA viruses.

Table 58–1Stages of Virus Replication and Possible Targets of Action of Antiviral Agents
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Table 58–1 Stages of Virus Replication and Possible Targets of Action of Antiviral Agents
STAGE OF REPLICATION CLASSES OF SELECTIVE INHIBITORS

Cell entry

 Attachment

 Penetration

 Soluble receptor decoys, antireceptor antibodies, fusion protein inhibitors

Uncoating

 Release of viral genome

 Ion channel blockers, capsid stabilizers

Transcription of viral genomea

 Transcription of viral messenger RNA

 Replication of viral genome

 Inhibitors of viral DNA polymerase, RNA polymerase, reverse transcriptase, helicase, primase, or integrase

Translation of viral proteins

 Regulatory proteins (early)

 Structural proteins (late)

Interferons, antisense oligonucleotides, ribozymes

Inhibitors of regulatory proteins

Post-translational modifications

 Proteolytic cleavage

 Myristoylation, glycosylation

 Protease inhibitors

Assembly of virion components

Release

 Budding, cell lysis

Interferons, assembly protein inhibitors

Neuraminidase inhibitors, antiviral antibodies, cytotoxic lymphocytes

aDepends on specific replication strategy of virus, but virus-specified enzyme required for part of process.

figure 58–1

Replicative cycles of DNA (A) and RNA (B) viruses. The replicative cycles of herpesvirus (A) and influenza (B) are examples of DNA-encoded and RNA-encoded viruses, respectively. Sites of action of antiviral agents also are shown. cDNA, complementary DNA; cRNA, complementary RNA; DNAp, DNA polymerase; mRNA, messenger RNA; RNAp, RNA polymerase; vRNA, viral RNA. The symbol

image indicates a block to virus growth. A. Replicative cycles of herpes simplex virus, a DNA virus, and the probable sites of action of antiviral agents. Herpesvirus replication is a regulated multistep process. After infection, a small number of immediate-early genes are transcribed; these genes encode proteins that regulate their own synthesis and are responsible for synthesis of early genes involved in genome replication, such as thymidine kinases, DNA polymerases, etc. After DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed and encode proteins that either are incorporated into or aid in the assembly of progeny virions. B. Replicative cycles of influenza, an RNA virus, and the loci for effects of antiviral agents. The mammalian cell shown is an airway epithelial cell. The M2 protein of influenza virus allows an influx of hydrogen ions into the virion interior, which in turn promotes dissociation of the RNP (ribonuclear protein) segments and release into the cytoplasm (uncoating). Influenza virus mRNA synthesis requires a primer cleared from cellular mRNA and used by the viral RNAp complex. The neuraminidase ...

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