7R6J

Co-crystal structure of Chaetomium glucosidase with compound 1

This is a non-PDB format compatible entry.

Summary for 7R6J

• Entry DOI: 10.2210/pdb7r6j/pdb
• Descriptor: Chaetomium alpha glucosidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-[(3-{[3-methyl-5-(pyrimidin-2-yl)anilino]methyl}phenyl)methyl]piperidine-3,4,5-triol, ... (7 entities in total)
• Functional Keywords: alpha glucosidase i, hydrolase, inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Chaetomium thermophilum (strain DSM 1495 / CBS 144.50 / IMI 039719)
• Total number of polymer chains: 2
• Total formula weight: 190167.83

Authors

Karade, S.S.,Mariuzza, R.A. (deposition date: 2021-06-22, release date: 2022-07-06, Last modification date: 2024-11-20)

Primary citation

Karade, S.S.,Franco, E.J.,Rojas, A.C.,Hanrahan, K.C.,Kolesnikov, A.,Yu, W.,MacKerell Jr., A.D.,Hill, D.C.,Weber, D.J.,Brown, A.N.,Treston, A.M.,Mariuzza, R.A.
Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum alpha-Glucosidase I with Anti-SARS-CoV-2 Activity.
J.Med.Chem., 66:2744-2760, 2023

PubMed Abstract: Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.

PubMed: 36762932
DOI: 10.1021/acs.jmedchem.2c01750

Experimental method

X-RAY DIFFRACTION (1.905 Å)