N-substituted valiolamine derivatives as potent inhibitors of endoplasmic reticulum α-glucosidases I and II with antiviral activity

Journal article

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.

Authors: Karade, S; Hill, M; Kiappes, JL; Manne, R; Aakula, B

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 64
• Issue: 24
• Pages: 18010-18024
• Publication date: 2021-12-06
• Acceptance date: 2021-11-18
• DOI: 10.1021/acs.jmedchem.1c01377
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: FFR