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Targeting ER α-glucosidase I with a single-dose iminosugar treatment protects against lethal influenza and dengue virus infections
DOI:
10.1021/acs.jmedchem.0c00067
Authors:
Kelly
Warfield
(Emergent BioSolutions)
,
Dominic S.
Alonzi
(Oxford Glycobiology Institute, University of Oxford)
,
Johan C.
Hill
(Oxford Glycobiology Institute, University of Oxford)
,
Alessandro T.
Caputo
(Oxford Glycobiology Institute, University of Oxford)
,
Pietro
Roversi
(Oxford Glycobiology Institute, University of Oxford; Leicester Institute of Structural and Chemical Biology, University of Leicester)
,
John I.
Kiappes
(Oxford Glycobiology Institute, University of Oxford)
,
Nicholas
Sheets
(La Jolla Institute for Allergy and Immunology)
,
Matthew
Duchars
(Emergent BioSolutions)
,
Raymond
Dwek
(Oxford Glycobiology Institute, University of Oxford)
,
Julia
Biggins
(Integrated Biotherapeutics Inc.)
,
Dale L.
Barnard
(Utah State University)
,
Sujan
Shresta
(La Jolla Institute for Allergy and Immunology)
,
Anthony
Treston
(Emergent BioSolutions)
,
Nicole
Zitzmann
(Oxford Glycobiology Institute, University of Oxford)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
State:
Published (Approved)
Published:
March 2020
Diamond Proposal Number(s):
12346
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 et al. reported two siblings with a rare genetic defect in ER alpha-glucosidase I (ER Glu I) who showed resistance to viral infections, identifying ER Glu I as a key antiviral target. Here we show that a single dose of UV-4B (the hydrochloride salt form of N-(9′-methoxynonyl)-1- deoxynojirimycin; MON-DNJ) capable of inhibiting Glu I in vivo is sufficient to prevent death in mice infected with lethal viral doses, even when treatment is started as late as 48 hours post-infection. The first crystal structure of mammalian ER Glu I will constitute the basis for the development of potent and selective inhibitors. Targeting ER Glu I with UV-4B derived compounds may alter treatment paradigms for acute viral disease through development of a single-dose therapeutic regime.
Journal Keywords: Endoplasmic Reticulum Quality Control; ER alpha-glucosidase I; antiviral; dengue virus; influenza
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I02-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)