Identification of global inhibitors of cellular glycosylation.

Autor: Sørensen DM; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Büll C; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.; Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands., Madsen TD; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Lira-Navarrete E; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.; The Institute for Biocomputation and Physics of Complex Systems (BIFI), Mariano Esquillor s/n, Campus Rio Ebro, 50018, Zaragoza, Spain.; Fundación ARAID, 50018, Zaragoza, Spain., Clausen TM; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.; John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA., Clark AE; Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA., Garretson AF; Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA., Karlsson R; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Pijnenborg JFA; Institute for Molecules and Materials, Department of Synthetic Organic Chemistry, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands., Yin X; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA., Miller RL; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Chanda SK; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA., Boltje TJ; Institute for Molecules and Materials, Department of Synthetic Organic Chemistry, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands., Schjoldager KT; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Vakhrushev SY; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Halim A; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark., Esko JD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA., Carlin AF; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA., Hurtado-Guerrero R; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.; The Institute for Biocomputation and Physics of Complex Systems (BIFI), Mariano Esquillor s/n, Campus Rio Ebro, 50018, Zaragoza, Spain.; Fundación ARAID, 50018, Zaragoza, Spain., Weigert R; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Clausen H; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark. hclau@sund.ku.dk., Narimatsu Y; Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark. yoshiki@sund.ku.dk.; GlycoDisplay ApS, Copenhagen, Denmark. yoshiki@sund.ku.dk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Feb 20; Vol. 14 (1), pp. 948. Date of Electronic Publication: 2023 Feb 20.
DOI: 10.1038/s41467-023-36598-7
Abstrakt: Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: