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Research Themes Drug discovery

Tackling influenza

PSI-SGKB [doi:10.1038/fa_psisgkb.2009.23]
Featured Article - June 2009
Short description: Structural studies reveal a new target for anti-influenza drugs that should work whatever the influenza virus strain.Nature 458, 909-913 (2009)

Novel influenza viruses entering the human population can pose a considerable threat to health. Of the 421 human cases of influenza due to the H5N1 avian influenza virus reported since 2003, 257 have been fatal. In the current 'swine flu' epidemic with its center in Mexico, 4702 cases have been reported and 53 people have died as of 11 May 2009.

The influenza virus multiplies its RNA genome within the nucleus of infected host cells through the action of the viral RNA-dependent RNA polymerase. Understanding exactly how influenza virus multiplies is essential for the development of new anti-influenza drugs.

Ribbon representation showing the PA-Nter structure. The structure is coloured according to secondary structure elements: alpha-helices are pink, beta-strands are purple, and loops are green. The magnesium ion is shown by a silver sphere and the three water molecules are indicated by black dots. (PDB 2IXS, 1WDJ

The influenza polymerase consists of three proteins: PA, PB1 and PB2. Until now, the endonuclease activity of the polymerase was thought to be contained within subunit PB1. But two studies published recently in Nature 1 2 show that it is subunit PA that harbors the endonuclease activity.

Both Yuan et al. 1 and Dias et al. 2 crystallized and solved the structure of the amino-terminal domain of PA, called PA-Nter. Yuan et al. report the 2.2 Å structure of the N-terminal 197 residues of PA from an avian influenza H5N1 virus, whereas Dias et al. solved the structure of the N-terminal 209 residues of an H3N2 strain at 2 Å resolution.

Structural comparisons, together with mutagenesis and functional studies by both groups showed that PA-Nter has an endonuclease site and suggest that the enzymatic activity requires either a magnesium or a manganese ion. The active site contains a histidine and a cluster of three acidic residues that are conserved in all influenza PA proteins sequenced and is formed by a PDXEK active-site motif.

The high conservation of this endonuclease active site among influenza strains indicates that PA-Nter could be an important potential target for the design of new anti-influenza therapeutics. Dias et al. show that the endonuclease activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the viral polymerase.

It is likely that other regions of the polymerase regulate the endonuclease activity of PA-Nter, because of the tight cooperation between capped RNA binding, 3′ and 5′ end viral RNA binding and the endonuclease activity.

These results establish a unique role for the PA subunit of influenza virus polymerase and contradict the widely held view that the endonuclease active site is located in the PB1 subunit. These structures provide a new potential target for designing anti-influenza therapeutics, which are urgently needed because of increasing problems of resistance to anti-influenza drugs such as oseltamivir (Tamiflu) and zanamivir (Relenza).

Related article

Antiviral evasion: The crystal structure of influenza A protein NS1A

Maria Hodges

References

  1. P. Yuan et al. Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site.
    Nature 458, 909-913 (2009). doi:10.1038/nature07720

  2. A. Dias et al. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.
    Nature 458, 914-919 (2009). doi:10.1038/nature07745

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