Identification of global inhibitors of cellular glycosylation

Daniel Madriz Sørensen, Christian Büll, Thomas D. Madsen, Erandi Lira-Navarrete, Thomas Mandel Clausen, Alex E. Clark, Aaron F. Garretson, Richard Karlsson, Johan F. A. Pijnenborg, Xin Yin, Rebecca L. Miller, Sumit K. Chanda, Thomas J. Boltje, Katrine T. Schjoldager, Sergey Y. Vakhrushev, Adnan Halim, Jeffrey D. Esko, Aaron F. Carlin, Ramon Hurtado-Guerrero, Roberto Weigert, Henrik Clausen () and Yoshiki Narimatsu ()
Additional contact information
Daniel Madriz Sørensen: University of Copenhagen
Christian Büll: University of Copenhagen
Thomas D. Madsen: University of Copenhagen
Erandi Lira-Navarrete: University of Copenhagen
Thomas Mandel Clausen: University of Copenhagen
Alex E. Clark: Department of Medicine, University of California, San Diego
Aaron F. Garretson: Department of Medicine, University of California, San Diego
Richard Karlsson: University of Copenhagen
Johan F. A. Pijnenborg: Radboud University Nijmegen
Xin Yin: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road
Rebecca L. Miller: University of Copenhagen
Sumit K. Chanda: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road
Thomas J. Boltje: Radboud University Nijmegen
Katrine T. Schjoldager: University of Copenhagen
Sergey Y. Vakhrushev: University of Copenhagen
Adnan Halim: University of Copenhagen
Jeffrey D. Esko: University of California, San Diego
Aaron F. Carlin: University of California, San Diego
Ramon Hurtado-Guerrero: University of Copenhagen
Roberto Weigert: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Henrik Clausen: University of Copenhagen
Yoshiki Narimatsu: University of Copenhagen

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36598-7

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