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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 47 µM binding affinity for human UGGT1 in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 µM. 5M-8OH-Q likely binds to the site of recognition of the first GlcNAc residue of the substrate N -glycan. 5M-8OH-Q binding to CtUGGTGT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.


Journal article




Elsevier (Cell Press)

Publication Date



University of Massachusetts Amherst - Department of Biochemistry and Molecular Biology, University of Oxford - Oxford Glycobiology Institute, University of Trento - Department of Cellular, Computational and Integrative Biology, University of Edinburgh - Wellcome Centre for Cell Biology, University of Buenos Aires (UBA) - Facultad de Ciencias Exactas y Naturales, University of Milano - Department of Biosciences, University of Milan - Department of Biosciences


UGGT inhibitor, CtUGGTGT24, 5-[(morpholin-4-yl)methyl]quinolin-8-ol, X-ray crystallography, fragment-based lead discovery, saturation transfer difference NMR spectroscopy, fluorescence polarisation anisotropy, ligand-enhanced fluorescence, microscale thermophoresis