title: Strain-specific antiviral activity of iminosugars against human influenza A viruses.
abstract: OBJECTIVE
  Drugs that target host cell processes can be employed to complement drugs that specifically target viruses, and iminosugar compounds that inhibit host α-glucosidases have been reported to show antiviral activity against multiple viruses. Here the effect and mechanism of two iminosugar α-glucosidase inhibitors, N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-deoxynojirimycin (NN-DNJ), on human influenza A viruses was examined.
  
  
  METHODS
  The viruses examined were a recently circulating seasonal influenza A(H3N2) virus strain A/Brisbane/10/2007, an older H3N2 strain A/Udorn/307/72, and A/Lviv/N6/2009, a strain representative of the currently circulating pandemic influenza A(H1N1)pdm09 virus.
  
  
  RESULTS
  The inhibitors had the strongest effect on Brisbane/10 and NN-DNJ was more potent than NB-DNJ. Both compounds showed antiviral activity in cell culture against three human influenza A viruses in a strain-specific manner. Consistent with its action as an α-glucosidase inhibitor, NN-DNJ treatment resulted in an altered glycan processing of influenza haemagglutinin (HA) and neuraminidase (NA), confirmed by MS. NN-DNJ treatment was found to reduce the cell surface expression of the H3 subtype HA. The level of sialidase activity of NA was reduced in infected cells, but the addition of exogenous sialidase to the cells did not complement the NN-DNJ-mediated inhibition of virus replication. Using reassortant viruses, the drug susceptibility profile was determined to correlate with the origin of the HA.
  
  
  CONCLUSIONS
  NN-DNJ inhibits influenza A virus replication in a strain-specific manner that is dependent on the HA.
authors.affiliation: Division of Virology, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK Division of Physical Biochemistry, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK Department of Biological Sciences, Gibbet Hill Campus, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Harvey
authors.affiliation: Confocal Imaging and Analysis Laboratory, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Division of Physical Biochemistry, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: P B
authors.initials: PB
authors.lastname: Rosenthal
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: N
authors.initials: N
authors.lastname: Zitzmann
authors.affiliation: Division of Virology, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, UK jmccaul@nimr.mrc.ac.uk.
authors.forename: J W
authors.initials: JW
authors.lastname: McCauley
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology; D008826:Microbial Sensitivity Tests; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin; C059896:miglustat
keywords: N-butyl-deoxynojirimycin; N-nonyl-deoxygalactojirimycin; N-nonyl-deoxynojirimycin; NB-DNJ; NN-DGJ; NN-DNJ