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Article ; Online: Antiviral effects of deoxynojirimycin (DNJ)-based iminosugars in dengue virus-infected primary dendritic cells.

Perera, Nilanka / Brun, Juliane / Alonzi, Dominic S / Tyrrell, Beatrice E / Miller, Joanna L / Zitzmann, Nicole

2022 Volume 199, Page(s) 105269

Abstract: Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived ... ...

Abstract	Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived macrophages (MDMΦs). Given the important role played by DCs in innate immune defense against DENV, the antiviral effects of three deoxynojirimycin (DNJ) derivatives (NN-DNJ, EOO-DNJ and 2THO-DNJ) and a deoxygalactonojirimycin (DGJ) negative control were evaluated in DENV-infected primary human monocyte-derived immature DCs (imDCs). DNJ- but not DGJ-derivatives elicited antiviral activity in DENV-infected imDCs, similar to that observed in MDMΦs. The DNJ-derivatives inhibited DENV secretion in a dose-dependent manner. Endoplasmic reticulum (ER) α-glucosidase I inhibition by DNJ-derived iminosugars, at concentrations of 3.16 μM, correlated with a reduction in the specific infectivity of virions that were still secreted, as well as a reduction in DENV-induced tumour necrosis factor alpha secretion. This suggests iminosugar-mediated ER α-glucosidase I inhibition may give rise to further benefits during DENV infection, beyond the reduction in viral secretion associated with ER α-glucosidase II inhibition.
MeSH term(s)	1-Deoxynojirimycin/pharmacology ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Dendritic Cells ; Dengue/drug therapy ; Dengue Virus ; Endoplasmic Reticulum ; Humans ; Macrophages
Chemical Substances	Antiviral Agents ; 1-Deoxynojirimycin (19130-96-2)
Language	English
Publishing date	2022-02-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2022.105269
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Article ; Online: Iminosugar antivirals: the therapeutic sweet spot.

Alonzi, Dominic S / Scott, Kathryn A / Dwek, Raymond A / Zitzmann, Nicole

Biochemical Society transactions

2017 Volume 45, Issue 2, Page(s) 571–582

Abstract: Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein ... ...

Abstract	Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein folding cycle. Viral glycoproteins are thus prevented from interacting with the protein-folding machinery leading to misfolding and an antiviral effect against a wide range of different viral families. As iminosugars target host enzymes, they should be refractory to mutations in the virus. Iminosugars therefore have great potential for development as broad-spectrum antiviral therapeutics. We outline the mechanism giving rise to the antiviral activity of iminosugars, the current progress in the development of iminosugar antivirals and future prospects for this field.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Clinical Trials as Topic ; Communicable Diseases/drug therapy ; Communicable Diseases/virology ; Endoplasmic Reticulum/enzymology ; Glucosidases/antagonists & inhibitors ; Humans ; Imino Sugars/chemistry ; Imino Sugars/pharmacology ; Imino Sugars/therapeutic use ; Protein Folding/drug effects ; Viral Proteins/chemistry
Chemical Substances	Antiviral Agents ; Imino Sugars ; Viral Proteins ; Glucosidases (EC 3.2.1.-)
Language	English
Publishing date	2017-04-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20160182
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Article: Therapeutic targets for inhibitors of glycosylation.

Alonzi, Dominic S / Butters, Terry D

Chimia

2011 Volume 65, Issue 1-2, Page(s) 35–39

Abstract: Small molecule inhibitors of glycoconjugate metabolism are being exploited for therapeutic benefit in a number of human disorders. As examples of this class of compound, imino sugars, as monosaccharide mimics, have a number of advantages for compound ... ...

Abstract	Small molecule inhibitors of glycoconjugate metabolism are being exploited for therapeutic benefit in a number of human disorders. As examples of this class of compound, imino sugars, as monosaccharide mimics, have a number of advantages for compound design and synthesis to define biological activity. As polyhydroxylated molecules, each chiral centre offers manipulation to generate isomers with restricted or enhanced mimicry, and the endocyclic nitrogen atom is readily modified to gain selectivity, increase potency or improve pharmacodynamics. This review focuses on the discovery of imino sugars that have considerable potential for treating a diverse range of diseases, from lysosomal storage disorders diabetes and cystic fibrosis to viral pathogenesis, and addresses the mechanism of action that is dictated by structural modification.
MeSH term(s)	Disease ; Glycosylation/drug effects ; Humans ; Imino Sugars/chemical synthesis ; Imino Sugars/chemistry ; Imino Sugars/pharmacology ; Molecular Structure
Chemical Substances	Imino Sugars
Language	English
Publishing date	2011-04-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1516-7
ISSN	0009-4293
ISSN	0009-4293
DOI	10.2533/chimia.2011.35
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Article: Assessing Antigen Structural Integrity through Glycosylation Analysis of the SARS-CoV-2 Viral Spike.

Brun, Juliane / Vasiljevic, Snežana / Gangadharan, Bevin / Hensen, Mario / V Chandran, Anu / Hill, Michelle L / Kiappes, J L / Dwek, Raymond A / Alonzi, Dominic S / Struwe, Weston B / Zitzmann, Nicole

ACS central science

2021 Volume 7, Issue 4, Page(s) 586–593

Abstract: Severe acute respiratory syndrome coronavirus 2 is the causative pathogen of the COVID-19 pandemic which as of March 29, 2021, has claimed 2 776 175 lives worldwide. Vaccine development efforts focus on the viral trimeric spike glycoprotein as the main ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 is the causative pathogen of the COVID-19 pandemic which as of March 29, 2021, has claimed 2 776 175 lives worldwide. Vaccine development efforts focus on the viral trimeric spike glycoprotein as the main target of the humoral immune response. Viral spikes carry glycans that facilitate immune evasion by shielding specific protein epitopes from antibody neutralization, and antigen efficacy is influenced by spike glycoprotein production in vivo. Therefore, immunogen integrity is important for glycoprotein-based vaccine candidates. Here, we show how site-specific glycosylation differs between virus-derived spikes, wild-type, non-stabilized spikes expressed from a plasmid with a CMV promoter and tPA signal sequence, and commonly used recombinant, engineered spike glycoproteins. Furthermore, we show that their distinctive cellular secretion pathways result in different protein glycosylation and secretion patterns, including shedding of spike monomeric subunits for the non-stabilized wild-type spike tested, which may have implications for the resulting immune response and vaccine design.
Language	English
Publishing date	2021-03-31
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.1c00058
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Article ; Online: Hydrophilic interaction liquid chromatography of anthranilic acid-labelled oligosaccharides with a 4-aminobenzoic acid ethyl ester-labelled dextran hydrolysate internal standard.

Neville, David C A / Alonzi, Dominic S / Butters, Terry D

Journal of chromatography. A

2012 Volume 1233, Page(s) 66–70

Abstract: Hydrophilic interaction liquid chromatography (HILIC) of fluorescently labelled oligosaccharides is used in many laboratories to analyse complex oligosaccharide mixtures. Separations are routinely performed using a TSK gel-Amide 80 HPLC column, and ... ...

Abstract	Hydrophilic interaction liquid chromatography (HILIC) of fluorescently labelled oligosaccharides is used in many laboratories to analyse complex oligosaccharide mixtures. Separations are routinely performed using a TSK gel-Amide 80 HPLC column, and retention times of different oligosaccharide species are converted to glucose unit (GU) values that are determined with reference to an external standard. However, if retention times were to be compared with an internal standard, consistent and more accurate GU values would be obtained. We present a method to perform internal standard-calibrated HILIC of fluorescently labelled oligosaccharides. The method relies on co-injection of 4-aminobenzoic acid ethyl ester (4-ABEE)-labelled internal standard and detection by UV absorption, with 2-AA (2-aminobenzoic acid)-labelled oligosaccharides. 4-ABEE is a UV chromophore and a fluorophore, but there is no overlap of the fluorescent spectrum of 4-ABEE with the commonly used fluorescent reagents. The dual nature of 4-ABEE allows for accurate calculation of the delay between UV and fluorescent signals when determining the GU values of individual oligosaccharides. The GU values obtained are inherently more accurate as slight differences in gradients that can influence retention are negated by use of an internal standard. Therefore, this paper provides the first method for determination of HPLC-derived GU values of fluorescently labelled oligosaccharides using an internal calibrant.
MeSH term(s)	Benzocaine/chemistry ; Chromatography, High Pressure Liquid/methods ; Hydrolysis ; Oligosaccharides/analysis ; Oligosaccharides/chemistry ; Reference Standards ; Spectrophotometry, Ultraviolet ; ortho-Aminobenzoates/chemistry
Chemical Substances	Oligosaccharides ; ortho-Aminobenzoates ; anthranilic acid (0YS975XI6W) ; Benzocaine (U3RSY48JW5)
Language	English
Publishing date	2012-04-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1171488-8
ISSN	1873-3778 ; 0021-9673
ISSN (online)	1873-3778
ISSN	0021-9673
DOI	10.1016/j.chroma.2012.02.007
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Article: Structural Insights into the Broad-Spectrum Antiviral Target Endoplasmic Reticulum Alpha-Glucosidase II.

Caputo, Alessandro T / Alonzi, Dominic S / Kiappes, John L / Struwe, Weston B / Cross, Alice / Basu, Souradeep / Darlot, Benoit / Roversi, Pietro / Zitzmann, Nicole

Advances in experimental medicine and biology

2018 Volume 1062, Page(s) 265–276

Abstract: Targeting the host-cell endoplasmic reticulum quality control (ERQC) pathway is an effective broad-spectrum antiviral strategy. The two ER resident α-glucosidases whose sequential action permits entry in this pathway are the targets of glucomimetic ... ...

Abstract	Targeting the host-cell endoplasmic reticulum quality control (ERQC) pathway is an effective broad-spectrum antiviral strategy. The two ER resident α-glucosidases whose sequential action permits entry in this pathway are the targets of glucomimetic inhibitors. Knowledge of the molecular details of the ER α-glucosidase II (α-Glu II) structure was limited. We determined crystal structures of a trypsinolytic fragment of murine α-Glu II, alone and in complex with key catalytic cycle ligands, and four different broad-spectrum antiviral iminosugar inhibitors, two of which are currently in clinical trials against dengue fever. The structures highlight novel portions of the enzyme outside its catalytic pocket which contribute to its activity and substrate specificity. These crystal structures and hydrogen-deuterium exchange mass spectrometry of the murine ER alpha glucosidase II heterodimer uncover the quaternary arrangement of the enzyme's α- and β-subunits, and suggest a conformational rearrangement of ER α-Glu II upon association of the enzyme with client glycoproteins.
MeSH term(s)	Animals ; Endoplasmic Reticulum/enzymology ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/immunology ; Endoplasmic Reticulum/virology ; Host-Pathogen Interactions ; Humans ; Virus Diseases/enzymology ; Virus Diseases/genetics ; Virus Diseases/immunology ; Virus Diseases/virology ; Virus Physiological Phenomena ; Viruses/genetics ; alpha-Glucosidases/chemistry ; alpha-Glucosidases/genetics ; alpha-Glucosidases/immunology
Chemical Substances	alpha-Glucosidases (EC 3.2.1.20)
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-981-10-8727-1_19
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Article ; Online: Urinary glycan markers for disease.

Alonzi, Dominic S / Su, Ying-Hsiu / Butters, Terry D

Biochemical Society transactions

2011 Volume 39, Issue 1, Page(s) 393–398

Abstract: Robust assays for the isolation and characterization of urinary FOS (free oligosaccharides) have been developed to screen patients for altered protein and/or lipid glycosylation. A FOS analysis can therefore identify potential biomarkers for ... ...

Abstract	Robust assays for the isolation and characterization of urinary FOS (free oligosaccharides) have been developed to screen patients for altered protein and/or lipid glycosylation. A FOS analysis can therefore identify potential biomarkers for hepatocellular carcinoma, since variations in glycosylation as a result of tumorigenecity should be detectable in the FOS of patients. HCC (hepatocellular carcinoma) accounts for 80-90% of all liver cancers. It occurs more often in men than women and occurs mostly in people 50-60 years old. The disease is more common in parts of Africa and Asia than in North or South America and Europe. Using a combination of solid-phase extraction techniques and affinity chromatography, followed by separation of urinary FOS by NP (normal phase)-HPLC and HIAX (hydrophilic interaction and anion-exchange)-HPLC, more than 200 different species have been identified in patient samples. The high incidence of small sialylated oligosaccharides in HCC patients suggests that pro-inflammatory markers may be detected as early indicators of disease progression. In addition, the methods developed here to isolate and analyse excreted glycoprotein- and glycosphingolipid-bound oligosaccharides have been used to characterize changes in metabolic processes that underlie a number of human genetic disorders. The ability to predict disease status in microlitre amounts of readily available non-invasive urine samples indicates that rapid methods for screening can be developed.
MeSH term(s)	Biomarkers/chemistry ; Biomarkers/urine ; Carcinoma, Hepatocellular/diagnosis ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/urine ; Chromatography, High Pressure Liquid/methods ; Disease Progression ; Glycosylation ; Humans ; Liver Neoplasms/diagnosis ; Liver Neoplasms/pathology ; Liver Neoplasms/urine ; Polysaccharides/chemistry ; Polysaccharides/urine
Chemical Substances	Biomarkers ; Polysaccharides
Language	English
Publishing date	2011-01-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST0390393
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Article ; Online: Targeting Endoplasmic Reticulum α-Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections.

Warfield, Kelly L / Alonzi, Dominic S / Hill, Johan C / Caputo, Alessandro T / Roversi, Pietro / Kiappes, J L / Sheets, Nicholas / Duchars, Matthew / Dwek, Raymond A / Biggins, Julia / Barnard, Dale / Shresta, Sujan / Treston, Anthony M / Zitzmann, Nicole

Journal of medicinal chemistry

2020 Volume 63, Issue 8, Page(s) 4205–4214

Abstract: Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, ... ...

Abstract	Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, Sadat
MeSH term(s)	Animals ; Dengue/drug therapy ; Dengue/enzymology ; Dengue/prevention & control ; Dengue Virus/drug effects ; Dengue Virus/enzymology ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/enzymology ; Glycoside Hydrolase Inhibitors/administration & dosage ; Humans ; Influenza, Human/drug therapy ; Influenza, Human/enzymology ; Influenza, Human/prevention & control ; Mice, 129 Strain ; Mice, Inbred BALB C ; Protein Structure, Secondary ; alpha-Glucosidases/metabolism
Chemical Substances	Glycoside Hydrolase Inhibitors ; glucosidase I (EC 3.2.1.-) ; alpha-Glucosidases (EC 3.2.1.20)
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c00067
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Article ; Online: Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target.

Sobala, Łukasz F / Fernandes, Pearl Z / Hakki, Zalihe / Thompson, Andrew J / Howe, Jonathon D / Hill, Michelle / Zitzmann, Nicole / Davies, Scott / Stamataki, Zania / Butters, Terry D / Alonzi, Dominic S / Williams, Spencer J / Davies, Gideon J

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 47, Page(s) 29595–29601

Abstract: Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from ... ...

Abstract	Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Bovine Virus Diarrhea-Mucosal Disease/drug therapy ; Cattle ; Cell Line ; Dengue Virus/drug effects ; Dogs ; Glucosidases/metabolism ; Glycosylation/drug effects ; Humans ; Madin Darby Canine Kidney Cells ; Mannosidases/chemistry ; Mannosidases/pharmacology ; Polysaccharides/metabolism ; Secretory Pathway/drug effects
Chemical Substances	Antiviral Agents ; Polysaccharides ; Glucosidases (EC 3.2.1.-) ; Mannosidases (EC 3.2.1.-)
Language	English
Publishing date	2020-11-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2013620117
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Article ; Online: Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*.

Zhu, Sha / Jagadeesh, Yerri / Tran, Anh Tuan / Imaeda, Shuki / Boraston, Alisdair / Alonzi, Dominic S / Poveda, Ana / Zhang, Yongmin / Désiré, Jérôme / Charollais-Thoenig, Julie / Demotz, Stéphane / Kato, Atsushi / Butters, Terry D / Jiménez-Barbero, Jesús / Sollogoub, Matthieu / Blériot, Yves

Chemistry (Weinheim an der Bergstrasse, Germany)

2021 Volume 27, Issue 44, Page(s) 11291–11297

Abstract: Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach ...

Abstract	Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.
MeSH term(s)	Acetylglucosaminidase ; Glycosides ; Humans ; Mucopolysaccharidosis III ; Rare Diseases
Chemical Substances	C-glycoside ; Glycosides ; alpha-N-acetyl-D-glucosaminidase (EC 3.2.1.50) ; Acetylglucosaminidase (EC 3.2.1.52)
Language	English
Publishing date	2021-07-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202101408
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