N‑Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α‑Glucosidases I and II with Antiviral Activity

Most
enveloped viruses rely on the host cell endoplasmic reticulum
(ER) quality control (QC) machinery for proper folding of glycoproteins.
The key ER α-glucosidases (α-Glu) I and II of the ERQC
machinery are attractive targets for developing broad-spectrum antivirals.
Iminosugars based on deoxynojirimycin have been extensively studied
as ER α-glucosidase inhibitors; however, other glycomimetic
compounds are less established. Accordingly, we synthesized a series
of N-substituted derivatives of valiolamine, the iminosugar scaffold
of type 2 diabetes drug voglibose. To understand the basis for up
to 100,000-fold improved inhibitory potency, we determined high-resolution
crystal structures of mouse ER α-GluII in complex with valiolamine
and 10 derivatives. The structures revealed extensive interactions
with all four α-GluII subsites. We further showed that N-substituted
valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors
of the ERQC machinery as candidates for developing potential broad-spectrum
therapeutics against the existing and emerging viruses.