Guanosine Diphosphate Fucose (GDP-Fucose) Inhibitor Development Service at CD BioGlyco

GDP-Fucose is an important sugar nucleic acid substrate, which is produced in cells through two biosynthetic pathways. The first is the salvage pathway, in which free l-fucose is converted into GDP-fucose through the catalysis of fucokinase and fucose pyrophosphorylase. The second way is the de novo pathway, GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase-4-reductase (FX) and GDP-mannose 4,6-dehydratase (GMDS) catalyze GDP-mannose to generate GDP-fucose. GDP-Fucose participates in a variety of biological processes in cells, especially as a donor substrate in glycosylation reactions. Abnormal expression of fucosylated glycans is associated with a variety of diseases, so controlling fucose expression on living cells may help study and treat related diseases. CD BioGlyco has mature Glycosylation Inhibitor Development means and provides various types of GDP-fucose inhibitor development services.

• CD BioGlyco has developed a class of competitive GMDS inhibitors that directly target GDP-fucose. We synthesize cell-permeable fluorinated rhamnose 1-phosphate derivatives that are metabolized into GDP analogs to inhibit the de novo GDP-fucose biosynthetic pathway through competitive GMDS.
• We also synthesize a set of C2 or C6 fluorinated fucose analogs using l-fucose, l-galactose, or d-mannose as starting materials. Among them, 2-deoxy-2-fluoro-l-fucose, 6,6,6-trifluoro-l-fucose, and their full-O-acetylated derivatives also act as inhibitors of core fucosylation. Cell assays have shown that 6,6-difluoro-l-fucose and 6,6,6-trifluoro-l-fucose analogs have potent inhibitory effects on the proliferation of human colon cancer cells, which may be due to the inhibition of key enzymes (GMDS and FX) necessary for GDP-fucose biosynthesis.
• At the same time, CD BioGlyco has also developed related fucosylation inhibitors based on the salvage biosynthetic pathway of GDP-fucose, such as 1,3,4-tri-O-acetyl-2-deoxy-2-fluoro-l-fucose.
• In addition, CD BioGlyco provides specialized inhibitor evaluation services, we evaluate the inhibitory potency of the developed inhibitors in different cells using fucose-specific lectins (AAL and AOL) and analyze by flow cytometry.

Fig.1 GDP-Fucose inhibitor development service. (CD BioGlyco)

Publication

Technology: Chemoenzymatic method

Journal: Nature Communications

IF: 17.694

Published: 2021

Results: The authors synthesized 10 compounds using mannose and mannose-1-phosphate as precursors by chemoenzymatic methods, and then evaluated the inhibitory potency of produced compounds using lectins at different concentrations in three cell lines (THP-1, Jurkat, EL4). The authors determined the EC₅₀ value, and the results showed that non-phosphorylated compounds 1-5 did not exhibit any fucosylation inhibition. While in phosphorylation groups 6-10, monofluorinated, difluorinated, and tifluorinated derivatives 7-10 all showed inhibition of fucosylation.

Tab.1 EC₅₀ values in micromolar for fucose expression inhibition. (Pijnenborg, et al., 2021)

Applications

• Immunomodulation: GDP-Fucose participates in the glycosylation process on the surface of immune cells and regulates the functions of cells. By regulating GDP-fucose synthesis or related enzyme activity, the activation status, immune response type, and intensity of immune cells are affected, which may provide a new approach to immunotherapy.
• Inflammation and autoimmune diseases: Abnormal expression of GDP-fucose is associated with the occurrence and progression of inflammation and some autoimmune diseases. By developing GDP-fucose inhibitors, the functions of inflammatory cells and the release of inflammatory mediators are modulated, affecting the degree and duration of the inflammatory response.
• Glycosylation research: GDP-Fucose is one of the important substrates in glycosylation reactions. By developing GDP-fucose inhibitors, we interfere with or regulate the glycosylation modification of specific proteins or other biomolecules, thereby affecting their functions and interactions, and providing new strategies for the research of glycosylation-related diseases.

Advantages

• CD BioGlyco has professional scientific researchers who are familiar with GDP-fucose biosynthesis, enzyme catalytic reactions, and regulatory mechanisms of related enzymes and develop high-quality GDP-fucose inhibitors.
• CD BioGlyco is equipped with an efficient high-throughput screening that quickly screens and evaluates the inhibitory activity of a large number of GDP-fucose inhibitors.
• CD BioGlyco provides comprehensive, accurate, and detailed GDP-fucose inhibitor development reports to help clients understand the experimental process and make further decisions and planning based on research goals.

CD BioGlyco provides custom GDP-fucose inhibitor development plans based on client needs, including molecular design, screening methods, and verification strategies. Please feel free to contact us if you would like to explore more details about inhibitor development.