Fluorinated rhamnosides inhibit cellular fucosylation

Johan F. A. Pijnenborg, Emiel Rossing, Jona Merx, Marek J. Noga, Willem H. C. Titulaer, Nienke Eerden, Raisa Veizaj, Paul B. White, Dirk J. Lefeber and Thomas J. Boltje ()
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Johan F. A. Pijnenborg: Radboud University
Emiel Rossing: Radboud University
Jona Merx: Radboud University
Marek J. Noga: Radboud University Medical Center
Willem H. C. Titulaer: Radboud University
Nienke Eerden: Radboud University
Raisa Veizaj: Radboud University Medical Center
Paul B. White: Radboud University
Dirk J. Lefeber: Radboud University Medical Center
Thomas J. Boltje: Radboud University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract The sugar fucose is expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis via competitive GMDS inhibition. We demonstrate that cell permeable fluorinated rhamnose 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

Date: 2021
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DOI: 10.1038/s41467-021-27355-9

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