α-1,6-Fucosyltransferase (FUT8) Inhibitor Development Service at CD BioGlyco

The single human enzyme FUT8 is the only enzyme that modifies this modification by the addition of α-1,6-conjugated fucose to the N-glycans. In addition, FUT8 plays an important role in certain cancers, tumor cell production, and metastasis. CD BioGlyco will design and develop FUT8 inhibitors by exploring the structure of FUT8 and further resolving its biological function.

• Development of FUT8 inhibitors
  First, we explore the specific binding receptor for FUT8 based on the process of fucoidan glycosylation occurring in fucoidan. We find that the receptor specificity of FUT8 requires the presence of a terminal GlcNAc portion on the α-1,6 arm of the N-glycans, and we use gene knockdown and other methods to remove the GlcNAc portion of the N-glycans, thereby inhibiting their biological activity.
  Next, we establish a library of FUT8 inhibitors using compounds with a GlcNAc structure at the end of the molecule. At the same time, we use animal models, cellular models, and immunological methods to investigate the ability of the compounds in the library to interfere with or inhibit FUT8.
  Finally, we use a high throughput screening technique to screen for specific FUT8 inhibitors.
• FUT8 inhibitor assay
  We use bioinformatics databases and online tools to analyze the structural features of FUT8 inhibitors. We analyze the physicochemical properties, steric structures, protein interaction networks, and pathways of FUT8 inhibitors. This is conducive to expanding the screening of FUT8 inhibitors.

Fig.1 FUT8 inhibitor development service. (CD BioGlyco)

Publication

Technology: The crystal structure of FUT8 is complex with GDP and the dual antenna complex N-glycan (G0) to provide insight into substrate recognition and catalysis.

Journal: Nature Communications

IF: 16.6

Published: 2020

Results: FUT8 complexed with GDP and a biantennary complex N-glycan (G0) crystals of HsFUT8 were obtained in a complex containing GDP and G2 glycans. The resulting crystals allowed us to solve the structure at high resolution (1.95 Å) and to interpret the density map. The asymmetric unit of the G2 crystals contains two molecules of HsFUT8, which are arranged in a dimer with two molecules from neighboring AUs through direct contact between their corresponding N-terminal coiled-coil structural domains. The FUT8 follows the S_N2 mechanism and deploys a series of loops and α-helices, both of which contribute to the formation of the binding site. The exosome formed by one of the loops and the SH3 structural domain is responsible for recognizing branched-chain sugars, making specific contact with the α-1,3 arm GlcNAc, a feature required for catalysis.

Fig.2 Overall structure of HsFUT8 complexed to GDP and G0. (García-García, et al., 2020)

Advantages

• We design multiple protocols for the development of α-1,6 fucosyltransferase inhibitors to ensure client satisfaction.
• Our R&D technology supports the high quality, customization, and mass production of inhibitors.

CD BioGlyco has the advanced knowledge in glycobiology to provide Glycosylation Inhibitor Development Services to our clients. We have diversified contents in the field of glycosylation inhibitor development, such as Capping Modification Inhibitor Development Service, O-Glycosylation Inhibitor Development Service, and so on. Please feel free to contact us for more detailed information.

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