Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention

Abstract

In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.

Figure 1

The life cycle of the influenza virus. Shown are the targets of chemotherapeutic intervention. Anti-influenza-virus compounds fall into different classes according to their molecular target of interaction: neuraminidase inhibitors, M2 ion channel blockers (adamantanamine derivatives), IMP dehydrogenase inhibitors, interferon and siRNAs, and RNA polymerase (and endonuclease) inhibitors. Abbreviation: N, neuraminidase. Reproduced, with permission, from Ref. .

Figure 2

Major classes of anti-influenza-virus compounds. Shown are typical examples of compounds for the different classes.

Figure 3

Potential double-, triple- and quadruple-drug combinations of currently available anti-influenza-virus compounds. Drug combination regimens are aimed at synergizing antiviral action, diminishing (toxic) side effects and/or reducing the risk of developing drug resistance.