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Publication Abstract from PubMed

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 CtUGGT(GT24) "WY" conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 muM binding affinity for CtUGGT(GT24)in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 muM. 5M-8OH-Q binding to CtUGGT(GT24) 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.

A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint.,Guay KP, Ibba R, Kiappes JL, Vasiljevic S, Boni F, De Benedictis M, Zeni I, Le Cornu JD, Hensen M, Chandran AV, Kantsadi AL, Caputo AT, Blanco Capurro JI, Bayo Y, Hill JC, Hudson K, Lia A, Brun J, Withers SG, Marti M, Biasini E, Santino A, De Rosa M, Milani M, Modenutti CP, Hebert DN, Zitzmann N, Roversi P iScience. 2023 Sep 20;26(10):107919. doi: 10.1016/j.isci.2023.107919. eCollection , 2023 Oct 20. PMID:37822503^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.