iScience (Oct 2023)
A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
- Kevin P. Guay,
- Roberta Ibba,
- J.L. Kiappes,
- Snežana Vasiljević,
- Francesco Bonì,
- 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 Martí,
- Emiliano Biasini,
- Angelo Santino,
- Matteo De Rosa,
- Mario Milani,
- Carlos P. Modenutti,
- Daniel N. Hebert,
- Nicole Zitzmann,
- Pietro Roversi
Affiliations
- Kevin P. Guay
- Department of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA
- Roberta Ibba
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK; Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23A, 07100 Sassari, Italy
- J.L. Kiappes
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Snežana Vasiljević
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Francesco Bonì
- Institute of Biophysics, IBF-CNR Unit of Milano, via Celoria 26, 20133 Milano, Italy
- Maria De Benedictis
- Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, 73100 Lecce, Italy
- Ilaria Zeni
- Department of Cellular, Computational and Integrative Biology, University of Trento, Povo, 38123 Trento, Italy
- James D. Le Cornu
- Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- Mario Hensen
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Anu V. Chandran
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Anastassia L. Kantsadi
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Alessandro T. Caputo
- Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, 343 Royal Parade, Parkville, VIC 3052, Australia
- Juan I. Blanco Capurro
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
- Yusupha Bayo
- Department of Biosciences, University of Milano, via Celoria 26, 20133 Milano, Italy
- Johan C. Hill
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Kieran Hudson
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
- Andrea Lia
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK; Institute of Biophysics, IBF-CNR Unit of Milano, via Celoria 26, 20133 Milano, Italy
- Juliane Brun
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK
- Stephen G. Withers
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
- Marcelo Martí
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina
- Emiliano Biasini
- Department of Cellular, Computational and Integrative Biology, University of Trento, Povo, 38123 Trento, Italy; Dulbecco Telethon Institute, University of Trento, Povo, 38123 Trento, Italy
- Angelo Santino
- Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, 73100 Lecce, Italy
- Matteo De Rosa
- Institute of Biophysics, IBF-CNR Unit of Milano, via Celoria 26, 20133 Milano, Italy
- Mario Milani
- Institute of Biophysics, IBF-CNR Unit of Milano, via Celoria 26, 20133 Milano, Italy
- Carlos P. Modenutti
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina; Corresponding author
- Daniel N. Hebert
- Department of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA; Corresponding author
- Nicole Zitzmann
- Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK; Corresponding author
- Pietro Roversi
- Institute of Agricultural Biology and Biotechnology, IBBA-CNR Unit of Milano, via Bassini 15, 20133 Milano, Italy; Leicester Institute of Chemical and Structural Biology and Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, LE1 7HR Leicester, UK; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 10
p. 107919
Abstract
Summary: 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.
