Abstract
It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident α-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER α-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 μM. We further demonstrate that monocyclic glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose-mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum-resident α-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that inhibition of ER α-glucosidases prevents release of virus and is the primary antiviral mechanism of action of iminosugars against DENV.
Highlights
Iminosugars are considered to be promising candidates for broad-spectrum antiviral activity because of their presumed mechanism of action as glycoprotein processing inhibitors [1]. 1-Deoxynojirimycin (DNJ) iminosugar derivatives possess glucose stereochemistry and inhibit infectious virus production in vitro of viruses including dengue virus (DENV) [2,3,4,5,6,7], hepatitis B virus (HBV) [8,9], hepatitis C virus (HCV) [10], human immunodeficiency virus (HIV) [11], and influenza A virus [12]
Current treatment of dengue virus infection is supportive; iminosugars have been widely investigated as an antiviral strategy
The means by which these molecules are thought to exert their antiviral effects is through inhibition of host-resident glycoprotein processing enzymes, the endoplasmic reticulum-resident α-glucosidases, but many iminosugars are capable of inhibiting host glycolipid processing and are utilized clinically for the treatment of lysosomal storage disorders such as Gaucher’s and Niemann-Pick type C diseases
Summary
Iminosugars are considered to be promising candidates for broad-spectrum antiviral activity because of their presumed mechanism of action as glycoprotein processing inhibitors [1]. 1-Deoxynojirimycin (DNJ) iminosugar derivatives possess glucose stereochemistry and inhibit infectious virus production in vitro of viruses including dengue virus (DENV) [2,3,4,5,6,7], hepatitis B virus (HBV) [8,9], hepatitis C virus (HCV) [10], human immunodeficiency virus (HIV) [11], and influenza A virus [12]. Bicyclic iminosugars possessing glucostereochemistry, such as castanospermine, inhibit infectious virus production in vitro [11,13,14,15] Antiviral efficacy of both bicylic and monocyclic iminosugars has been further demonstrated in vivo, against DENV infection, with protection in lethal mouse models conferred by post-exposure therapeutic administration of N-butyl-DNJ (NB-DNJ, Miglustat, Zavesca) [5], N-(9-methoxynonyl)-DNJ (UV4, MON-DNJ) [16], and 6-O-butanoyl-castanospermine (BuCAST, celgosivir) [17,18]. These promising in vitro and in vivo results have led to clinical trials of both MON-DNJ and celgosivir as dengue therapeutics. Treatment should be relatively refractory to escape and be effective against many viruses possessing N-linked glycoproteins [1,19]
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