Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Type

Journal article

Journal

iScience

Publisher

Elsevier (Cell Press)

Publication Date

18/07/2023

Keywords

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