A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint

DOI: 10.1016/j.isci.2023.107919

Authors: Kevin P. Guay (University of Massachusetts) , Roberta Ibba (Oxford Glycobiology Institute; University of Sassari) , John L. Kiappes (Oxford Glycobiology Institute) , Snežana Vasiljević (Oxford Glycobiology Institut) , Francesco Bonì (IBF-CNR Unit of Milano) , Maria De Benedictis (C.N.R. Unit of Lecce) , Ilaria Zeni (University of Trento) , James D. Le Cornu (University of Edinburgh) , Mario Hensen (Oxford Glycobiology Institute) , Anu V. Chandran (Oxford Glycobiology Institute) , Anastassia L. Kantsadi (Oxford Glycobiology Institute) , Alessandro T. Caputo (Commonwealth Scientific and Industrial Research Organisation) , Juan I. Blanco Capurro (Universidad de Buenos Aires; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria) , Yusupha Bayo (University of Milano) , Johan C. Hill (Oxford Glycobiology Institute) , Kieran Hudson (University of British Columbia) , Andrea Lia (Oxford Glycobiology Institute; IBF-CNR Unit of Milano) , Juliane Brun (Oxford Glycobiology Institute) , Stephen G. Withers (University of British Columbia) , Marcelo Martí (Universidad de Buenos Aires; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria) , Emiliano Biasini (University of Trento) , Angelo Santino (C.N.R. Unit of Lecce) , Matteo De Rosa (IBF-CNR Unit of Milano) , Mario Milani (IBF-CNR Unit of Milano) , Carlos P. Modenutti (Universidad de Buenos Aires; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria) , Daniel N. Hebert (Diamond Light Source) , Nicole Zitzmann (Oxford Glycobiology Institute) , Pietro Roversi (IBBA-CNR Unit of Milano; University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Iscience

State: Published (Approved)
Published: September 2023
Diamond Proposal Number(s): 19758

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 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 CtUGGTGT24 in 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.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 27/09/2023 09:55

Documents:
1-s2.0-S258900422301996X-main.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)