Most antivirals currently available in the U.S. have been developed and approved in the last two decades. This flurry of activity was driven by successes in rational drug design and approval that began with the anti-herpesvirus nucleoside analog acyclovir, whose discovery and development resulted in the awarding of a Nobel Prize to Gertrude Elion and George Hitchings in 1988. Because viruses are obligatory intracellular microorganisms and rely on host biosynthetic machinery to reproduce, there were doubts about the possibility of developing antiviral drugs with selective toxicity, but those doubts have long been erased. Viruses are now obvious targets for effective antimicrobial chemotherapy, and it is certain that the number of available agents in this category will continue to increase.
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. There are distinct stages of viral replication and the classes of antiviral agents that can act at each stage (Table 58–1). Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell–directed nucleic acid or protein synthesis. Host cell molecules that are essential to viral replication also offer targets for intervention. Some effective antiviral agents (e.g., interferons; see Chapter 35) have multiple mechanisms of action that include modulation of host immune responses. Figure 58–1 gives a schematic diagram of the replicative cycle of typical DNA and RNA viruses. DNA viruses (and the diseases they cause) include poxviruses (smallpox), herpesviruses (chickenpox, shingles, oral and genital herpes), adenoviruses (conjunctivitis, sore throat), hepadnaviruses (hepatitis B [HBV]), and papillomaviruses (warts). Most DNA viruses enter the host cell nucleus, where the viral DNA is transcribed into mRNA by host cell polymerase; mRNA is translated in the usual host cell fashion into virus-specific proteins. An exception to this strategy are poxviruses, which carry their own RNA polymerase and replicate in the host cell cytoplasm.
Table 58-1Stages of Virus Replication and Possible Targets of Action of Antiviral Agents |Favorite Table|Download (.pdf) 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 ||Soluble receptor decoys, antireceptor antibodies, fusion protein inhibitors |
| Penetration || |
|Uncoating ||Ion channel blockers, capsid stabilizers |
| Release of viral genome || |
|Transcription of viral genomea ||Inhibitors of viral DNA polymerase, RNA polymerase, reverse |
| Transcription of viral messenger RNA ||transcriptase, helicase, primase, or integrase |
| Replication of viral genome || |
|Translation of viral proteins ||Interferons, antisense oligonucleotides, ribozymes |
| Regulatory proteins (early) ||Inhibitors of regulatory proteins |
| Structural proteins (late) || |
|Post-translational modifications || |
| Proteolytic cleavage ||Protease inhibitors |
| Myristoylation, glycosylation || |
|Assembly of virion components ||Interferons, assembly protein inhibitors |
|Release ||Neuraminidase inhibitors, antiviral antibodies, cytotoxic lymphocytes |
| Budding, cell lysis || |
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