Article
Author: Hensen, Mario ; Withers, Stephen G ; Martí, Marcelo ; Chandran, Anu V ; Vasiljević, Snežana ; Caputo, Alessandro T ; Zitzmann, Nicole ; Modenutti, Carlos P ; De Rosa, Matteo ; Bonì, Francesco ; De Benedictis, Maria ; Lia, Andrea ; Roversi, Pietro ; Ibba, Roberta ; Guay, Kevin P ; Kantsadi, Anastassia L ; Kiappes, J L ; Milani, Mario ; Hill, Johan C ; Santino, Angelo ; Zeni, Ilaria ; Hebert, Daniel N ; Brun, Juliane ; Blanco Capurro, Juan I ; Bayo, Yusupha ; Hudson, Kieran ; Le Cornu, James D ; Biasini, Emiliano
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 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 CtUGGTGT24in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 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.