1. Targeting Endoplasmic Reticulum α-Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections.
- Author
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Warfield KL, Alonzi DS, Hill JC, Caputo AT, Roversi P, Kiappes JL, Sheets N, Duchars M, Dwek RA, Biggins J, Barnard D, Shresta S, Treston AM, and Zitzmann N
- Subjects
- Animals, Dengue drug therapy, Dengue enzymology, Dengue Virus drug effects, Dengue Virus enzymology, Dose-Response Relationship, Drug, Endoplasmic Reticulum enzymology, Humans, Influenza, Human drug therapy, Influenza, Human enzymology, Mice, 129 Strain, Mice, Inbred BALB C, Protein Structure, Secondary, Dengue prevention & control, Endoplasmic Reticulum drug effects, Glycoside Hydrolase Inhibitors administration & dosage, Influenza, Human prevention & control, alpha-Glucosidases metabolism
- 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 α-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 h 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.
- Published
- 2020
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