N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity
Karade S., HILL M., KIAPPES JL., Manne R., Aakula B., ZITZMANN N., Warfield K., Treston A., Mariuzza R.
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.