Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes.
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 vir...
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ftdoajarticles:oai:doaj.org/article:b93e2aebbc4849b3869f8f19bc1be798 2023-05-15T15:14:52+02:00 Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. Andrew C Sayce Dominic S Alonzi Sarah S Killingbeck Beatrice E Tyrrell Michelle L Hill Alessandro T Caputo Ren Iwaki Kyoko Kinami Daisuke Ide J L Kiappes P Robert Beatty Atsushi Kato Eva Harris Raymond A Dwek Joanna L Miller Nicole Zitzmann 2016-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004524 https://doaj.org/article/b93e2aebbc4849b3869f8f19bc1be798 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4790851?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004524 https://doaj.org/article/b93e2aebbc4849b3869f8f19bc1be798 PLoS Neglected Tropical Diseases, Vol 10, Iss 3, p e0004524 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004524 2022-12-31T06:25:14Z 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 ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 3 e0004524 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Andrew C Sayce Dominic S Alonzi Sarah S Killingbeck Beatrice E Tyrrell Michelle L Hill Alessandro T Caputo Ren Iwaki Kyoko Kinami Daisuke Ide J L Kiappes P Robert Beatty Atsushi Kato Eva Harris Raymond A Dwek Joanna L Miller Nicole Zitzmann Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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 ... |
format |
Article in Journal/Newspaper |
author |
Andrew C Sayce Dominic S Alonzi Sarah S Killingbeck Beatrice E Tyrrell Michelle L Hill Alessandro T Caputo Ren Iwaki Kyoko Kinami Daisuke Ide J L Kiappes P Robert Beatty Atsushi Kato Eva Harris Raymond A Dwek Joanna L Miller Nicole Zitzmann |
author_facet |
Andrew C Sayce Dominic S Alonzi Sarah S Killingbeck Beatrice E Tyrrell Michelle L Hill Alessandro T Caputo Ren Iwaki Kyoko Kinami Daisuke Ide J L Kiappes P Robert Beatty Atsushi Kato Eva Harris Raymond A Dwek Joanna L Miller Nicole Zitzmann |
author_sort |
Andrew C Sayce |
title |
Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
title_short |
Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
title_full |
Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
title_fullStr |
Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
title_full_unstemmed |
Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases--Not Glycolipid Processing Enzymes. |
title_sort |
iminosugars inhibit dengue virus production via inhibition of er alpha-glucosidases--not glycolipid processing enzymes. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004524 https://doaj.org/article/b93e2aebbc4849b3869f8f19bc1be798 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 3, p e0004524 (2016) |
op_relation |
http://europepmc.org/articles/PMC4790851?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004524 https://doaj.org/article/b93e2aebbc4849b3869f8f19bc1be798 |
op_doi |
https://doi.org/10.1371/journal.pntd.0004524 |
container_title |
PLOS Neglected Tropical Diseases |
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10 |
container_issue |
3 |
container_start_page |
e0004524 |
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