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Fluorinated rhamnosides inhibit cellular fucosylation

Author

Listed:
  • 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
    Radboud University Medical Center)

  • Thomas J. Boltje

    (Radboud University)

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.

Suggested Citation

  • 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 & Thomas J. Boltje, 2021. "Fluorinated rhamnosides inhibit cellular fucosylation," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27355-9
    DOI: 10.1038/s41467-021-27355-9
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