title: Novel imino sugar α-glucosidase inhibitors as antiviral compounds.
abstract: Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Howe
authors.forename: N
authors.initials: N
authors.lastname: Smith
authors.forename: M J-R
authors.initials: MJ
authors.lastname: Lee
authors.forename: N
authors.initials: N
authors.lastname: Ardes-Guisot
authors.forename: B
authors.initials: B
authors.lastname: Vauzeilles
authors.forename: J
authors.initials: J
authors.lastname: Désiré
authors.forename: A
authors.initials: A
authors.lastname: Baron
authors.forename: Y
authors.initials: Y
authors.lastname: Blériot
authors.forename: M
authors.initials: M
authors.lastname: Sollogoub
authors.forename: D S
authors.initials: DS
authors.lastname: Alonzi
authors.forename: T D
authors.initials: TD
authors.lastname: Butters
mesh_terms: D017485:1-Deoxynojirimycin / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D001908:Diarrhea Viruses, Bovine Viral / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry; D065089:Glycoside Hydrolase Inhibitors; D006031:Glycosylation; D016174:Hepacivirus / Q000378:metabolism; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D014759:Viral Envelope Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars; D014759:Viral Envelope Proteins; C501633:deoxynojirimycine; C076551:gp53, bovine viral diarrhea virus; D017485:1-Deoxynojirimycin; D000520:alpha-Glucosidases; D005944:Glucosamine
keywords: Bovine viral diarrhea virus; Endoplasmic reticulum; Glucosidases; Imino sugars; Neoglycoconjugates