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.

1. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
2. Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
3. Present address: Centre for Biomolecular Sciences, University of St Andrews, St Andrews KY16 9ST, UK

Correspondence to: John J. Skehel¹ Correspondence and requests for materials should be addressed to J.J.S. (Email: mbrenna@nimr.mrc.ac.uk). 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.

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