title: 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.
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Rupert J
authors.initials: RJ
authors.lastname: Russell
authors.forename: Lesley F
authors.initials: LF
authors.lastname: Haire
authors.forename: David J
authors.initials: DJ
authors.lastname: Stevens
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Collins
authors.forename: Yi Pu
authors.initials: YP
authors.lastname: Lin
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Hay
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
authors.forename: John J
authors.initials: JJ
authors.lastname: Skehel
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001717:Birds / Q000821:virology; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D005585:Influenza in Birds / Q000188:drug therapy* / Q000821:virology; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D053139:Oseltamivir; D011487:Protein Conformation
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase