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Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

  • Joanna L. Miller
  • Beatrice E. Tyrrell
  • Nicole Zitzmann
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1062)

Abstract

The antiviral mechanism of action of iminosugars against many enveloped viruses, including dengue virus (DENV), HIV, influenza and hepatitis C virus, is believed to be mediated by inducing misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum-resident α-glucosidase enzymes. This leads to reduced secretion and/or infectivity of virions and hence lower viral titres, both in vitro and in vivo. Free oligosaccharide analysis from iminosugar-treated cells shows that antiviral activity correlates with production of mono- and tri-glucosylated sugars, indicative of inhibition of ER α-glucosidases. We demonstrate that glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. Galactose-mimicking iminosugars that have been tested do not inhibit glycoprotein processing but do inhibit glycolipid processing, and are not antiviral against DENV. By comparison, the antiviral activity of glucose-mimetic iminosugars that inhibit endoplasmic reticulum-resident α-glucosidases, but not glycolipid processing, demonstrates that inhibition of α-glucosidases is responsible for iminosugar antiviral activity against DENV. This monograph will review the investigations of many researchers into the mechanisms of action of iminosugars and the contribution of our current understanding of these mechanisms for optimising clinical delivery of iminosugars. The effects of iminosugars on enzymes other than glucosidases, the induction of ER stress and viral receptors will be also put into context. Data suggest that inhibition of α-glucosidases results in inhibited release of virus and is the primary antiviral mechanism of action of iminosugars against DENV.

Keywords

N-linked glycoproteins ER α-glucosidases Glucose-mimicking iminosugars Galactose-mimicking iminosugars ER-associated degradation Dengue virus 

Notes

Acknowledgements

JLM is supported by Oxford Glycobiology Institute Endowment, BET is supported by The Wellcome Trust [105402/Z/14/Z] and NZ is a Fellow of Merton College, Oxford.

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Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Joanna L. Miller
    • 1
  • Beatrice E. Tyrrell
    • 1
  • Nicole Zitzmann
    • 1
  1. 1.Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology InstituteUniversity of OxfordOxfordUK

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