Identification of global inhibitors of cellular glycosylation

Madriz Sørensen, D. ; Büll, C. ; Madsen, T. D. ; Lira-Navarrete, E. ; Clausen, T. M. ; Clark, A. E. ; Garretson, A. F. ; Karlsson, R. ; Pijnenborg, J. F. A. ; Yin, X. ; Miller, R. L. ; Chanda, S. K. ; Boltje, T. J. ; Schjoldager, K. T. ; Vakhrushev, S. Y. ; Halim, A. ; Esko, J. D. ; Carlin, A. F. ; Hurtado-Guerrero, R. ; Weigert, R. ; Clausen, H. ; Narimatsu, Y.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41467-023-36598-7

Año: 2023

Publicado en: Nature communications 14 (2023), 948 [19 pp.]
ISSN: 2041-1723

Factor impacto SCIMAGO: 4.887 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA-FEDER/E34-R17
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP58-18
Financiación: info:eu-repo/grantAgreement/EC/FP7/609409/EU/Supporting transnational mobility within the European life sciences by cofunding of the EMBO Fellowship Programme/LTFCOFUND2013
Financiación: info:eu-repo/grantAgreement/EC/H2020/787684/EU/Generation of a Cell-Based Sialoglycan Array to Decipher Biological Interactions and Functions of the Human Sialome/Sialoglycan Array
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2016-75633-P
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-105451GB-I00

Tipo y forma: Article (Published version)