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)