title: Iminosugars: Promising therapeutics for influenza infection.
abstract: Influenza virus causes three to five million severe respiratory infections per year in seasonal epidemics, and sporadic pandemics, three of which occurred in the twentieth century and are a continuing global threat. Currently licensed antivirals exclusively target the viral neuraminidase or M2 ion channel, and emerging drug resistance necessitates the development of novel therapeutics. It is believed that a host-targeted strategy may combat the development of antiviral drug resistance. To this end, a class of molecules known as iminosugars, hydroxylated carbohydrate mimics with the endocyclic oxygen atom replaced by a nitrogen atom, are being investigated for their broad-spectrum antiviral potential. The influenza virus glycoproteins, hemagglutinin and neuraminidase, are susceptible to inhibition of endoplasmic reticulum α-glucosidases by certain iminosugars, leading to reduced virion production or infectivity, demonstrated by in vitro and in vivo studies. In some experiments, viral strain-specific effects are observed. Iminosugars may also inhibit other host and virus targets with antiviral consequences. While investigations of anti-influenza iminosugar activities have been conducted since the 1980s, recent successes of nojirimycin derivatives have re-invigorated investigation of the therapeutic potential of iminosugars as orally available, low cytotoxicity, effective anti-influenza drugs.
authors.affiliation: a Department of Biochemistry , University of Oxford Medical Sciences Division , Oxford , United Kingdom of Great Britain and Northern Ireland.
authors.forename: Beatrice Ellen
authors.identifier: http://orcid.org/0000-0003-2912-6419
authors.initials: BE
authors.lastname: Tyrrell
authors.affiliation: a Department of Biochemistry , University of Oxford Medical Sciences Division , Oxford , United Kingdom of Great Britain and Northern Ireland.
authors.forename: Andrew Cameron
authors.initials: AC
authors.lastname: Sayce
authors.affiliation: b Antiviral Research and Development, Emergent BioSolutions Inc , Gaithersburg , MD , United States.
authors.forename: Kelly Lyn
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: a Department of Biochemistry , University of Oxford Medical Sciences Division , Oxford , United Kingdom of Great Britain and Northern Ireland.
authors.forename: Joanna Louise
authors.identifier: http://orcid.org/0000-0002-4383-4641
authors.initials: JL
authors.lastname: Miller
authors.affiliation: a Department of Biochemistry , University of Oxford Medical Sciences Division , Oxford , United Kingdom of Great Britain and Northern Ireland.
authors.forename: Nicole
authors.identifier: http://orcid.org/0000-0003-1969-4949
authors.initials: N
authors.lastname: Zitzmann
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000627:therapeutic use*; D006031:Glycosylation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D009439:Neuraminidase / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus; D017485:1-Deoxynojirimycin; D009439:Neuraminidase; D000520:alpha-Glucosidases; C013626:nojirimycin
keywords: Influenza; N-glycosylation; hemagglutinin; iminosugars; neuraminidase