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

Most enveloped viruses rely on host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER alpha-glucosidases (alpha-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 alpha-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 the up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER alpha-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interaction with all four alpha-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 existing and emerging viruses.