A Quinolin-8-Ol Sub-Millimolar Inhibitor of UGGT, the ER Glycoprotein Folding Quality Control Checkpoint

Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding Quality Control (ERQC) checkpoint enzyme, UDP-Glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. We carried out a fragment-based lead discovery screen via X-ray crystallography and discovered that the small molecule 5-[(morpholin4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGTGT24 ‘WY’ conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 613 µM binding affinity for human UGGT1 in vitro as measured by saturation transfer difference NMR spectroscopy. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 µM. 5M-8OH-Q likely works as a competitive inhibitor, binding to the site of recognition of the first GlcNAc residue of the substrate N-glycan. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.