Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α‑Glucosidase I with Anti-SARS-CoV‑2 Activity

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.