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

Overview

Journal iScience

Publisher Cell Press

Date 2023 Oct 12

PMID 37822503

Authors

Kevin P Guay

Roberta Ibba

J L Kiappes

Snezana Vasiljevic

Francesco Boni

Maria De Benedictis

Ilaria Zeni

James D Le Cornu

Mario Hensen

Anu V Chandran

Anastassia L Kantsadi

Alessandro T Caputo

Juan I Blanco Capurro

Yusupha Bayo

Johan C Hill

Kieran Hudson

Andrea Lia

Juliane Brun

Stephen G Withers

Marcelo Marti

Emiliano Biasini

Angelo Santino

Matteo De Rosa

Mario Milani

Carlos P Modenutti

Daniel N Hebert

Nicole Zitzmann

Pietro Roversi

Affiliations

Soon will be listed here.

Abstract

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. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a UGGT "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 UGGT as measured by ligand-enhanced fluorescence. , 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to UGGT appears to be mutually exclusive to M5-9 glycan binding in an competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.

Citing Articles

Rescue of secretion of rare-disease-associated misfolded mutant glycoproteins in UGGT1 knock-out mammalian cells.

Tax G, Guay K, Pantalone L, Ceci M, Solda T, Hitchman C Traffic. 2024; 25(1):e12927.

PMID: 38272446 PMC: 10832616. DOI: 10.1111/tra.12927.

Rescue of secretion of a rare-disease associated mis-folded mutant glycoprotein in knock-out mammalian cells.

Tax G, Guay K, Solda T, Hitchman C, Hill J, Vasiljevic S bioRxiv. 2023; .

PMID: 37398215 PMC: 10312515. DOI: 10.1101/2023.05.30.542711.

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