Karade, SS; Hill, ML; Kiappes, JL; Manne, R; Aakula, B; Zitzmann, N; Warfield, KL; ... Mariuzza, RA; + view all Karade, SS; Hill, ML; Kiappes, JL; Manne, R; Aakula, B; Zitzmann, N; Warfield, KL; Treston, AM; Mariuzza, RA; - view fewer (2021) N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity. Journal of Medicinal Chemistry , 64 (24) pp. 18010-18024. 10.1021/acs.jmedchem.1c01377.

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Abstract

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.

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