7KB8

Co-crystal structure of alpha glucosidase with compound 8

Summary for 7KB8

• Entry DOI: 10.2210/pdb7kb8/pdb
• Descriptor: Isoform 2 of Neutral alpha-glucosidase AB, Glucosidase 2 subunit beta, (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-5-[(4-{[2-nitro-4-(triazan-1-yl)phenyl]amino}butyl)amino]cyclohexane-1,2,3,4-tetrol, ... (9 entities in total)
• Functional Keywords: alpha glucosidase ii, endoplasmic reticulum, hydrolase, inhibitor complex
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 4
• Total formula weight: 350970.56

Authors

Karade, S.S.,Mariuzza, R.A. (deposition date: 2020-10-01, release date: 2021-10-06, Last modification date: 2024-10-23)

Primary citation

Karade, S.S.,Hill, M.L.,Kiappes, J.L.,Manne, R.,Aakula, B.,Zitzmann, N.,Warfield, K.L.,Treston, A.M.,Mariuzza, R.A.
N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum alpha-Glucosidases I and II with Antiviral Activity.
J.Med.Chem., 64:18010-18024, 2021

PubMed 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 . This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.

PubMed: 34870992
DOI: 10.1021/acs.jmedchem.1c01377

Experimental method

X-RAY DIFFRACTION (2.385 Å)