2. Academic Validation
  3. Fluorinated rhamnosides inhibit cellular fucosylation

Fluorinated rhamnosides inhibit cellular fucosylation

  • Nat Commun. 2021 Dec 2;12(1):7024. doi: 10.1038/s41467-021-27355-9.
Johan F A Pijnenborg # 1,  Emiel Rossing # 1,  Jona Merx 1,  Marek J Noga 2,  Willem H C Titulaer 1,  Nienke Eerden 1,  Raisa Veizaj 3,  Paul B White 1,  Dirk J Lefeber 2 3,  Thomas J Boltje 4
Affiliations

Affiliations

  • 1 Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands.
  • 2 Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands.
  • 3 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands.
  • 4 Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands. thomas.boltje@ru.nl.
  • # Contributed equally.
PMID: 34857733 DOI: 10.1038/s41467-021-27355-9
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.

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