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

doi:10.1016/j.isci.2023.107919

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

iScience. 2023 Sep 20;26(10):107919. doi: 10.1016/j.isci.2023.107919. eCollection 2023 Oct 20.

Authors

Kevin P Guay¹, Roberta Ibba^{2

3}, J L Kiappes², Snežana Vasiljević², Francesco Bonì⁴, Maria De Benedictis⁵, Ilaria Zeni⁶, James D Le Cornu⁷, Mario Hensen², Anu V Chandran², Anastassia L Kantsadi², Alessandro T Caputo⁸, Juan I Blanco Capurro^{9

10}, Yusupha Bayo¹¹, Johan C Hill², Kieran Hudson¹², Andrea Lia^{2

4}, Juliane Brun², Stephen G Withers¹², Marcelo Martí^{9

10}, Emiliano Biasini^{6

13}, Angelo Santino⁵, Matteo De Rosa⁴, Mario Milani⁴, Carlos P Modenutti^{9

10}, Daniel N Hebert¹, Nicole Zitzmann², Pietro Roversi^{14

15}

Affiliations

¹ Department of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA.
² Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK.
³ Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23A, 07100 Sassari, Italy.
⁴ Institute of Biophysics, IBF-CNR Unit of Milano, via Celoria 26, 20133 Milano, Italy.
⁵ Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, 73100 Lecce, Italy.
⁶ Department of Cellular, Computational and Integrative Biology, University of Trento, Povo, 38123 Trento, Italy.
⁷ Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
⁸ Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, 343 Royal Parade, Parkville, VIC 3052, Australia.
⁹ Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina.
¹⁰ Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Universitaria, Pab. II (CE1428EHA), Buenos Aires, Argentina.
¹¹ Department of Biosciences, University of Milano, via Celoria 26, 20133 Milano, Italy.
¹² Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
¹³ Dulbecco Telethon Institute, University of Trento, Povo, 38123 Trento, Italy.
¹⁴ Institute of Agricultural Biology and Biotechnology, IBBA-CNR Unit of Milano, via Bassini 15, 20133 Milano, Italy.
¹⁵ 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.

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 CtUGGT_GT24 "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 CtUGGT_GT24in 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 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.

Keywords: Cell biology; Chemistry; Functional aspects of cell biology.

Abstract

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