Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity.
J Med Chem
; 66(4): 2744-2760, 2023 02 23.
Article
in English
| MEDLINE | ID: covidwho-2242001
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 in vitro 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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
1-Deoxynojirimycin
/
Alpha-Glucosidases
/
Glycoside Hydrolase Inhibitors
/
COVID-19
Type of study:
Prognostic study
Limits:
Animals
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2023
Document Type:
Article
Affiliation country:
Acs.jmedchem.2c01750
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