The Iminosugar UV-4 is a Broad Inhibitor of Influenza A and B Viruses ex Vivo and in Mice

Warfield, Kelly L.; Barnard, Dale L.; Enterlein, Sven; Smee, Donald F.; Khaliq, Mansoora; Sampath, Aruna; Callahan, Michael V.; Ramstedt, Urban; Day, Craig W.

doi:10.3390/v8030071

Cited by 33 publications

(55 citation statements)

References 24 publications

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“…Our results provide basic virology to help advance the prospect of antiviral therapeutics. Reduced viral load and disease have been achieved in other flaviviruses through inhibition of host glycosylation using iminosugars (Perry et al, ; Warfield et al, ; Warfield et al, ) and in diverse RNA viruses and retroviruses by lowering cholesterol levels (Pollock et al, ). Recent work has demonstrated glycosylation of the immature ZIKV capsid (Prasad et al, ) and our results using EM and tomography, in combination with results from the Bartenschlager lab (Cortese et al, ), further demonstrate fundamental similarities in the ZIKV life cycle to those of other flaviviruses.…”

Section: Discussionmentioning

confidence: 99%

Zika virus induced cellular remodelling

Rossignol

Peters

Connor

et al. 2017

Cellular Microbiology

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Summary Zika virus (ZIKV) has been associated with morbidities such as Guillain-Barré, infant microcephaly, and ocular disease. The spread of this positive-sense, single-stranded RNA virus and its growing public health threat underscore gaps in our understanding of basic ZIKV virology. To advance knowledge of the virus replication cycle within mammalian cells, we use serial section three-dimensional electron tomography to demonstrate the widespread remodeling of intracellular membranes upon infection with ZIKV. We report extensive structural rearrangements of the endoplasmic reticulum and reveal stages of the ZIKV viral replication cycle. Structures associated with RNA genome replication and virus assembly are observed integrated within the endoplasmic reticulum, and we show viruses in transit through the Golgi apparatus for viral maturation, and subsequent cellular egress. This study characterizes in detail the three-dimensional ultrastructural organization of the ZIKV replication cycle stages. Our results show close adherence of the ZIKV replication cycle to the existing flavivirus replication paradigm.

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Section: Discussionmentioning

confidence: 99%

Zika virus induced cellular remodelling

Rossignol

Peters

Connor

et al. 2017

Cellular Microbiology

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“…This study was able to show that both N B-DNJ and M O N-DNJ were safe and well tolerated, even at high doses, in guinea pigs. Subsequent to these experiments being performed, M O N-DNJ was also shown to be tolerable via oral dosing in mice up to 150 mg/kg TID for 7 days [48], which can be extrapolated with body surface adjustment to be ~56 mg/kg in guinea pigs. Both drugs were able to inhibit ER α-glucosidases in vivo , as demonstrated by the detection of FOS in liver samples taken at the end of the experiment.…”

Section: Discussionmentioning

confidence: 99%

Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

et al. 2016

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The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

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“…MON-DNJ was developed to be a more potent yet similarly non-toxic derivative of N-butyl-DNJ (NB-DNJ) through alkyl chain elongation and oxygenation [44,45] and has demonstrated more potent in vivo antiviral effects than NB-DNJ against dengue virus. MON-DNJ has antiviral activity against a range of viruses in vitro, and in vivo efficacy in animal models against dengue [51,89] and influenza virus [74,88]. A Phase I single-ascending dose clinical trial of MON-DNJ in humans (NCT02061358) has recently been completed, in which 64 volunteers received a single oral dose ranging from 3-1000 mg, with no serious adverse events reported.…”

Section: Clinical Trials Of Iminosugars Against Denguementioning

confidence: 99%

Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

Miller

Tyrrell

Zitzmann

2018

Advances in Experimental Medicine and Biology

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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.

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The Iminosugar UV-4 is a Broad Inhibitor of Influenza A and B Viruses ex Vivo and in Mice

Cited by 33 publications

References 24 publications

Zika virus induced cellular remodelling

Zika virus induced cellular remodelling

Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

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