Fluorinated rhamnosides inhibit cellular fucosylation

Area of Science:

• Biochemistry and Molecular Biology
• Glycobiology
• Chemical Biology

Background:

• Fucose is a crucial sugar on mammalian cell membranes, involved in vital physiological functions.
• Abnormal fucosylation is linked to diseases including cancer, inflammation, and infections.
• Developing tools to modulate fucose expression is essential for biological research and therapeutics.

Purpose of the Study:

• To develop novel inhibitors targeting the de novo biosynthesis of GDP-fucose.
• To investigate the potential of these inhibitors in modulating cellular fucosylation.
• To provide new tools for understanding the biological roles of fucose and developing therapies.

Main Methods:

• Designed and synthesized fluorinated rhamnose 1-phosphate derivatives (Fucotrim I & II).
• Investigated the compounds as metabolic prodrugs targeting GDP-fucose biosynthesis.
• Assessed the inhibition of GDP-mannose pyrophosphorylase (GMDS) and cellular fucosylation.

Main Results:

• Fucotrim I & II act as prodrugs, metabolized to GDP-mannose derivatives.
• These derivatives competitively inhibit GMDS, a key enzyme in de novo GDP-fucose synthesis.
• Demonstrated efficient inhibition of cellular fucosylation by Fucotrim I & II.

Conclusions:

• Fluorinated rhamnose derivatives (Fucotrim I & II) are effective inhibitors of cellular fucosylation.
• These compounds provide a novel strategy for targeting de novo GDP-fucose biosynthesis.
• The developed inhibitors are valuable tools for glycobiology research and therapeutic development.