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  • Review Article
  • Published:

Antiviral agents active against influenza A viruses

Nature Reviews Drug Discovery volume 5, pages 1015–1025 (2006)Cite this article

Key Points

  • Several drugs are available that could be used, either alone or in combination, for the treatment (prophylaxis or therapy) of an influenza pandemic. These include adamantan(amin)e derivatives (amantadine), neuraminidase inhibitors (zanamivir and oseltamivir), ribavirin and interferon.

  • Amantadine was the first synthetic compound shown to inhibit influenza-virus replication. It blocks the migration of H+ ions into the interior of the virus particles within endosomes, a process that is needed for uncoating to occur.

  • Neuraminidase inhibitors such as oseltamivir and zanamivir interfere with the release of progeny influenza virions from the surface of infected host cells. In doing so, the neuraminidase inhibitors prevent virus infection of new host cells and thereby halt the spread of infection in the respiratory tract.

  • Ribavirin targets a cellular enzyme — inosine 5′-monophosphate dehydrogenase, which has a key role in the biosynthesis of GTP and viral RNA synthesis — and is active against both human and avian influenza viruses.

  • In addition to the available drugs, attempts to further design and develop new antivirals should be intensified, whether based on known molecular targets, such as the neuraminidase or viral uncoating process, or on as-yet relatively unexplored targets such as viral RNA polymerase.

Abstract

The recent outbreaks of avian influenza A (H5N1) virus, its expanding geographic distribution and its ability to transfer to humans and cause severe infection have raised serious concerns about the measures available to control an avian or human pandemic of influenza A. In anticipation of such a pandemic, several preventive and therapeutic strategies have been proposed, including the stockpiling of antiviral drugs, in particular the neuraminidase inhibitors oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline). This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses.

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Figure 1: The two mechanisms by which pandemic influenza originates.
Figure 2: Inhibition of the influenza-virus replication cycle by antiviral agents.
Figure 3: Adamantan(amin)e derivatives as antiviral drugs.
Figure 4: Viral neuraminidase inhibition.
Figure 5: Neuraminidase inhibitors.
Figure 6: IMP dehydrogenase inhibition.
Figure 7: Influenza-virus RNA-polymerase inhibitors.

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Acknowledgements

I thank C. Callebaut for her invaluable editorial assistance.

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  1. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, B-3000, Belgium

    Erik De Clercq

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FURTHER INFORMATION

Avian flu web focus

Glossary

HXNY

In the naming system for virus strains, H refers to haemagglutinin and N to neuraminidase.

Alveoli

Lung structures responsible for gas (O2 ↔ CO2) exchange.

Transition state analogue

A structural mimic of the intermediary state between reactant(s) and product(s) in a given reaction.

PEGylation

Addition of poly(ethylene glycol) (PEG) groups to proteins can increase their resistance to proteolytic degradation, improve their water solubility and reduce their antigenicity.

Prodrug

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. It is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

Small interfering RNAs

(siRNAs). Small (∼20 nucleotide) RNA constructs that interfere with RNA translation.

Phosphorothioate oligonucleotides

Antisense oligonucleotides in which phosphate groups are replaced by thiophosphate groups.

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De Clercq, E. Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5, 1015–1025 (2006). https://doi.org/10.1038/nrd2175

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