Targeting Endoplasmic Reticulum α‑Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections

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.