Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity
- Resource Type
- Article
- Authors
- Karade, Sharanbasappa S.; Franco, Evelyn J.; Rojas, Ana C.; Hanrahan, Kaley C.; Kolesnikov, Alexander; Yu, Wenbo; MacKerell, Alexander D.; Hill, Daniel C.; Weber, David J.; Brown, Ashley N.; Treston, Anthony M.; Mariuzza, Roy A.
- Source
- Journal of Medicinal Chemistry; 20230101, Issue: Preprints
- Subject
- Language
- ISSN
- 00222623; 15204804
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 vitroto 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.