The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design

Abstract

The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.

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Figure 1: Genetic and structural relationships between neuraminidases from different influenza viruses.
Figure 2: Molecular surfaces of group-1 and group-2 neuraminidases with bound oseltamivir showing the 150-cavity in the group-1 structure that arises because of the distinct conformation of the 150-loop.
Figure 3: Oseltamivir binding to the active sites of group-1 neuraminidases.
Figure 4: Locations of the oseltamivir resistance mutations found in group-1 and group-2 neuraminidases.

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Acknowledgements

This work was supported by the MRC (UK) and by an International Partnership Research Award in Veterinary Epidemiology from the Wellcome Trust. R.J.R. acknowledges the Wellcome Trust and the University of St Andrews for support and Biocryst for supply of peramivir. We thank P. Walker for assistance with data collection and preparation of the manuscript, and Rigaku (Europe) and CRUK (Lincoln's Inn) for access to data collection facilities.

Author information

Correspondence to John J. Skehel.

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Competing interests

Coordinates have been deposited with the Protein Data Bank and the relevant accession codes (2HTY, 2HU0, 2HU4, 2HT5, 2HTR, 2HT7, 2HT8, 2HTQ, 2HTU, 2HTV and 2HTW) are described in Supplementary Table 1. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Comparison of the superposed active sites of Influenza B neuraminidase with that of the Influenza N9 neuraminidase. (JPG 74 kb)

Supplementary Figure 2

The ‘open’ structure of N1 with bound oseltamivir. (JPG 109 kb)

Supplementary Figure 3

Binding of DANA, Zanamivir, and Peramivir neuraminidase inhibitors to the active sites of Group-1 and Group-2 NAs. (JPG 51 kb)

Supplementary Notes

This file contains Supplementary Table 1 and Supplementary Figure Legends. (DOC 47 kb)

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