In spite of the looming threat of resistant strains, there is no doubt that antibiotics have been hugely successful in the control of bacterial diseases. We have, however, been a lot less successful when it comes to finding a treatment for diseases caused by viruses; a quick revision of their modus operandi (Chapter 10) should make it clear why this is so. Viruses survive by entering a host cell and hijacking its replicative machinery, thus a substance interfering with the virus is likely to harm the host as well. A number of compounds have been developed however, which are able to act selectively on a viral target.
All antiviral agents act by interfering with some aspect of the virus's replication cycle. A number of such compounds have been found, but only a few have been approved for use in humans.
One of the first antiviral agents to be approved for use was amantidine, which inhibits uncoating of the influenza A virus by preventing the formation of acid conditions in the host cell's endocytotic vesicles (see Chapter 10). Its specificity for the virus is due to selective binding to M2, a matrix protein. Amantidine's efficacy is dependent on administration within the early stages of an infection. It can be administered prophylactically, but may have side-effects.
Most antiviral agents target nucleic acid synthesis, usually by acting as base analogues. These are molecules that are incorporated into viral nucleotides instead of the normal deoxynucleosides, disrupting synthesis because DNA polymerase is unable to act on them. The majority of viruses encode their own DNA polymerases, and the base analogues exert their effect by selectively inhibiting these, thus having little effect on that of the host cell. An example is acyclovir, which is an analogue of guanosine; it is converted to the nucleoside triphosphate by the action of thymidine kinase and then in this form acts as a competitive inhibitor of the 'correct' version (Figure 14.9). When the acyclovir nucleotide is incorporated into the viral DNA, there is no attachment point for the next nucleotide, so further elongation of the chain is prevented. Acyclovir exerts
Figure 14.9 Acyclovir inhibits viral DNA synthesis. (a) Acyclovir has a similar structure to the nucleoside deoxyguanosine, but lacks the -OH group (circled) necessary for chain extension. (b) Acyclovir needs to be phosphorylated to become active; virally encoded thymidine kinase is required for this. Acyclovir triphosphate (ACV-T) selectively inhibits viral, but not human, DNA polymerase. Any ACV-T that is incorported into viral DNA acts as a chain terminator
Figure 14.9 Acyclovir inhibits viral DNA synthesis. (a) Acyclovir has a similar structure to the nucleoside deoxyguanosine, but lacks the -OH group (circled) necessary for chain extension. (b) Acyclovir needs to be phosphorylated to become active; virally encoded thymidine kinase is required for this. Acyclovir triphosphate (ACV-T) selectively inhibits viral, but not human, DNA polymerase. Any ACV-T that is incorported into viral DNA acts as a chain terminator its selective action by having a much higher affinity for the viral polymerase than that of the host. It is used in the treatment of herpes simplex infections; unfortunately, in a scenario echoing our experience with antibiotics, resistant strains of herpes simplex virus have been shown to exist. This can be seen as even more serious than the emergence of antibiotic resistant bacteria, because the choice of alternative antiviral agents is so restricted. Vidarabine and azidothymidine (AZT) are other examples of base analogues. AZT (Retrovir) was one of the first substances shown to have an effect against HIV, which it does by preventing cDNA synthesis by the enzyme reverse transcriptase (see Chapter 10).
Zanamivir was approved by the US Food and Drug Administration (FDA) in 1999. It belongs to a new class of synthetic compounds called neuraminidase inhibitors, which act selectively against both influenza A and B viruses. They block the active site of the enzyme neuraminidase, preventing the release of new virus particles from infected cells, hence reducing the spread of the infection. Zanamivir is inhaled as a fine powder directly into the lungs of patients who are in the early stages of infection.
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