title: Structural basis for a class of nanomolar influenza A neuraminidase inhibitors.
abstract: The influenza virus neuraminidase (NA) is essential for the virus life cycle. The rise of resistance mutations against current antiviral therapies has increased the need for the development of novel inhibitors. Recent efforts have targeted a cavity adjacent to the catalytic site (the 150-cavity) in addition to the primary catalytic subsite in order to increase specificity and reduce the likelihood of resistance. This study details structural and in vitro analyses of a class of inhibitors that bind uniquely in both subsites. Crystal structures of three inhibitors show occupation of the 150-cavity in two distinct and novel binding modes. We believe these are the first nanomolar inhibitors of NA to be characterized in this way. Furthermore, we show that one inhibitor, binding within the catalytic site, offers reduced susceptibility to known resistance mutations via increased flexibility of a pendant pentyloxy group and the ability to pivot about a strong hydrogen-bonding network.
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, KY16 9ST, UK.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Kerry
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Rupert J M
authors.initials: RJ
authors.lastname: Russell
authors.forename: Nicole
authors.initials: N
authors.lastname: Bance
authors.forename: Masahiro
authors.initials: M
authors.lastname: Niikura
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D053139:Oseltamivir / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase