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

Kevin P. Guay, Roberta Ibba, JL Kiappes, 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, Snežana Vasiljević, Carlos P. Modenutti, Stephen G. Withers, Marcelo Martí, Emiliano Biasini, Angelo Santino, Daniel N. Hebert, Nicole Zitzmann, Pietro Roversi
doi: https://doi.org/10.1101/2022.06.21.496940
Kevin P. Guay
aDepartment of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts, United States
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Roberta Ibba
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
cDepartment of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23A, 07100, Sassari, Italy
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JL Kiappes
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Maria De Benedictis
dInstitute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy
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Ilaria Zeni
eDepartment of Cellular, Computational and Integrative Biology, University of Trento, 38123, Povo, TN, Italy
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James D. Le Cornu
fWellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
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Mario Hensen
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Anu V. Chandran
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Anastassia L. Kantsadi
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Alessandro T. Caputo
gBiomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, 343 Royal Parade, Parkville, Victoria, 3052, Australia
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Juan I. Blanco Capurro
hDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
iInstituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET. Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
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Yusupha Bayo
jDepartment of Biosciences, University of Milano, via Celoria 26, I-20133 Milano, Italy
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Johan C. Hill
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Kieran Hudson
kDepartment of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C. Canada V6T 1Z1
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Andrea Lia
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
dInstitute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy
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Snežana Vasiljević
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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Carlos P. Modenutti
hDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
iInstituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET. Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
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Stephen G. Withers
kDepartment of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C. Canada V6T 1Z1
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Marcelo Martí
hDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
iInstituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET. Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
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Emiliano Biasini
eDepartment of Cellular, Computational and Integrative Biology, University of Trento, 38123, Povo, TN, Italy
lDulbecco Telethon Institute, University of Trento, 38123, Povo, TN, Italy
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Angelo Santino
dInstitute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy
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Daniel N. Hebert
aDepartment of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts, United States
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  • For correspondence: dhebert@biochem.umass.edu nicole.zitzmann@bioch.ox.ac.uk pietro.roversi@ibba.cnr.it
Nicole Zitzmann
bOxford Glycobiology Institute, Biochemistry Department,University of Oxford, South Parks Road, Oxford OX1 3QU, England, United Kingdom
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  • For correspondence: dhebert@biochem.umass.edu nicole.zitzmann@bioch.ox.ac.uk pietro.roversi@ibba.cnr.it
Pietro Roversi
jDepartment of Biosciences, University of Milano, via Celoria 26, I-20133 Milano, Italy
mInstitute of Agricultural Biology and Biotechnology, IBBA-CNR Unit of Milano, via Bassini 15, I-20133 Milano, Italy
nLeicester Institute of Chemical and Structural Biology and Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7HR, England, United Kingdom
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  • For correspondence: dhebert@biochem.umass.edu nicole.zitzmann@bioch.ox.ac.uk pietro.roversi@ibba.cnr.it
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Abstract

The Endoplasmic Reticulum (ER) glycoprotein folding Quality Control (ERQC) machinery aids folding of glycoproteins in the ER. Misfolded glycoprotein recognition and ER-retention is mediated by the ERQC checkpoint enzyme, the 170 kDa 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. Towards the generation of selective UGGT inhibitors, we determined the crystal structures of the catalytic domain of Chaetomium thermophilum UGGT (CtUGGTGT24), alone and in complex with the inhibitor UDP-2-deoxy-2-fluoro-D-glucose (U2F). Using the CtUGGTGT24 crystals, we carried out a fragment-based lead discovery screen via X-ray crystallography and discovered that the small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGTGT24 'WY' conserved surface motif that is not present in other GT24 family glycosyltransferases. The 5M-8OH-Q molecule has a 613 μM binding affinity for human UGGT1in vitro as measured by saturation transfer difference NMR spectroscopy. The 5M-8OH-Q molecule inhibits both human UGGT1 and UGGT2 activity at concentrations higher than 750 μM in modified HEK293-6E cells. The compound is toxic in cellula and in planta at concentrations higher than 1 mM. A few off-target effects are also observed upon 5M-8OH-Q treatment. Based on an in silico model of the interaction between UGGT and its substrate N-glycan, the 5M-8OH-Q molecule likely works as a competitive inhibitor, binding to the site of recognition of the first GlcNAc residue of the substrate N-glycan.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.rcsb.org/structure/7ZKC

  • https://www.rcsb.org/structure/7ZLU

  • https://www.rcsb.org/structure/7ZLL

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
Kevin P. Guay, Roberta Ibba, JL Kiappes, 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, Snežana Vasiljević, Carlos P. Modenutti, Stephen G. Withers, Marcelo Martí, Emiliano Biasini, Angelo Santino, Daniel N. Hebert, Nicole Zitzmann, Pietro Roversi
bioRxiv 2022.06.21.496940; doi: https://doi.org/10.1101/2022.06.21.496940
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A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
Kevin P. Guay, Roberta Ibba, JL Kiappes, 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, Snežana Vasiljević, Carlos P. Modenutti, Stephen G. Withers, Marcelo Martí, Emiliano Biasini, Angelo Santino, Daniel N. Hebert, Nicole Zitzmann, Pietro Roversi
bioRxiv 2022.06.21.496940; doi: https://doi.org/10.1101/2022.06.21.496940

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