Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus.
Identifieur interne : 000983 ( Main/Exploration ); précédent : 000982; suivant : 000984Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus.
Auteurs : Joanna L. Miller [Royaume-Uni] ; Beatrice E. Tyrrell [Royaume-Uni] ; Nicole Zitzmann [Royaume-Uni]Source :
- Advances in experimental medicine and biology [ 0065-2598 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Dengue (enzymologie), Dengue (génétique), Dengue (immunologie), Dengue (virologie), Humains, Réticulum endoplasmique (enzymologie), Réticulum endoplasmique (génétique), Réticulum endoplasmique (immunologie), Réticulum endoplasmique (virologie), Virus de la dengue (génétique), Virus de la dengue (physiologie), alpha-Glucosidase (génétique), alpha-Glucosidase (immunologie).
- MESH :
- enzymologie : Dengue, Réticulum endoplasmique.
- génétique : Dengue, Réticulum endoplasmique, Virus de la dengue, alpha-Glucosidase.
- immunologie : Dengue, Réticulum endoplasmique, alpha-Glucosidase.
- physiologie : Virus de la dengue.
- virologie : Dengue, Réticulum endoplasmique.
- Animaux, Humains.
English descriptors
- KwdEn :
- Animals, Dengue (enzymology), Dengue (genetics), Dengue (immunology), Dengue (virology), Dengue Virus (genetics), Dengue Virus (physiology), Endoplasmic Reticulum (enzymology), Endoplasmic Reticulum (genetics), Endoplasmic Reticulum (immunology), Endoplasmic Reticulum (virology), Humans, Sugars (immunology), alpha-Glucosidases (genetics), alpha-Glucosidases (immunology).
- MESH :
- chemical , genetics : alpha-Glucosidases.
- chemical , immunology : Sugars, alpha-Glucosidases.
- enzymology : Dengue, Endoplasmic Reticulum.
- genetics : Dengue, Dengue Virus, Endoplasmic Reticulum.
- immunology : Dengue, Endoplasmic Reticulum.
- physiology : Dengue Virus.
- virology : Dengue, Endoplasmic Reticulum.
- Animals, Humans.
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.
DOI: 10.1007/978-981-10-8727-1_20
PubMed: 29845540
Affiliations:
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Le document en format XML
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Miller</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford, UK. joanna.miller@bioch.ox.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford</wicri:regionArea><placeName><settlement type="city">Oxford</settlement><region type="country">Angleterre</region><region type="comté" nuts="2">Oxfordshire</region></placeName><orgName type="university">Université d'Oxford</orgName></affiliation></author><author><name sortKey="Tyrrell, Beatrice E" sort="Tyrrell, Beatrice E" uniqKey="Tyrrell B" first="Beatrice E" last="Tyrrell">Beatrice E. Tyrrell</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford</wicri:regionArea><placeName><settlement type="city">Oxford</settlement><region type="country">Angleterre</region><region type="comté" nuts="2">Oxfordshire</region></placeName><orgName type="university">Université d'Oxford</orgName></affiliation></author><author><name sortKey="Zitzmann, Nicole" sort="Zitzmann, Nicole" uniqKey="Zitzmann N" first="Nicole" last="Zitzmann">Nicole Zitzmann</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, Antiviral Drug Discovery Group, Oxford Glycobiology Institute, University of Oxford, Oxford</wicri:regionArea><placeName><settlement type="city">Oxford</settlement><region type="country">Angleterre</region><region type="comté" nuts="2">Oxfordshire</region></placeName><orgName type="university">Université d'Oxford</orgName></affiliation></author></analytic><series><title level="j">Advances in experimental medicine and biology</title><idno type="ISSN">0065-2598</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Dengue (enzymology)</term><term>Dengue (genetics)</term><term>Dengue (immunology)</term><term>Dengue (virology)</term><term>Dengue Virus (genetics)</term><term>Dengue Virus (physiology)</term><term>Endoplasmic Reticulum (enzymology)</term><term>Endoplasmic Reticulum (genetics)</term><term>Endoplasmic Reticulum (immunology)</term><term>Endoplasmic Reticulum (virology)</term><term>Humans</term><term>Sugars (immunology)</term><term>alpha-Glucosidases (genetics)</term><term>alpha-Glucosidases (immunology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Dengue (enzymologie)</term><term>Dengue (génétique)</term><term>Dengue (immunologie)</term><term>Dengue (virologie)</term><term>Humains</term><term>Réticulum endoplasmique (enzymologie)</term><term>Réticulum endoplasmique (génétique)</term><term>Réticulum endoplasmique (immunologie)</term><term>Réticulum endoplasmique (virologie)</term><term>Virus de la dengue (génétique)</term><term>Virus de la dengue (physiologie)</term><term>alpha-Glucosidase (génétique)</term><term>alpha-Glucosidase (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>alpha-Glucosidases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Sugars</term><term>alpha-Glucosidases</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Dengue</term><term>Réticulum endoplasmique</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Dengue</term><term>Endoplasmic Reticulum</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Dengue</term><term>Dengue Virus</term><term>Endoplasmic Reticulum</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Dengue</term><term>Réticulum endoplasmique</term><term>Virus de la dengue</term><term>alpha-Glucosidase</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Dengue</term><term>Réticulum endoplasmique</term><term>alpha-Glucosidase</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Dengue</term><term>Endoplasmic Reticulum</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la dengue</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Dengue Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Dengue</term><term>Réticulum endoplasmique</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Dengue</term><term>Endoplasmic Reticulum</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Oxfordshire</li></region><settlement><li>Oxford</li></settlement><orgName><li>Université d'Oxford</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Miller, Joanna L" sort="Miller, Joanna L" uniqKey="Miller J" first="Joanna L" last="Miller">Joanna L. Miller</name></region><name sortKey="Tyrrell, Beatrice E" sort="Tyrrell, Beatrice E" uniqKey="Tyrrell B" first="Beatrice E" last="Tyrrell">Beatrice E. Tyrrell</name><name sortKey="Zitzmann, Nicole" sort="Zitzmann, Nicole" uniqKey="Zitzmann N" first="Nicole" last="Zitzmann">Nicole Zitzmann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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