Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

Advances in Experimental Medicine and Biology
Joanna L MillerNicole Zitzmann

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 activ...Continue Reading

Citations

Sep 29, 2020·Glycobiology·Elizabeth C ClarkeSteven B Bradfute
Mar 13, 2021·The Journal of General Virology·Ulrike BreitingerHans-Georg Breitinger
Aug 10, 2020·Antiviral Research·Lisa Evans DeWaldKelly L Warfield
Mar 12, 2021·Journal of Virology·Ichiro MisumiStanley M Lemon
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andreas WolfsgruberTanja M Wrodnigg
Dec 14, 2021·Journal of Medical Virology·Zhonglei Wang, Liyan Yang
Jan 1, 2019·Antiviral Research·Siew Pheng Lim

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Methods Mentioned

BETA
glycosylation
protein folding

Clinical Trials Mentioned

NCT01619969
NCT02569827
NCT02061358
NCT02696291

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