Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands.
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands.
Nat Commun. 2021 Dec 2;12(1):7024. doi: 10.1038/s41467-021-27355-9.
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.
糖基岩藻糖作为糖缀合物的一部分表达在哺乳动物细胞膜上，并介导重要的生理过程。糖基化异常表达的岩藻糖与癌症、炎症、感染和遗传疾病等病理学有关。需要调节活细胞上岩藻糖表达的工具来阐明岩藻糖的生物学作用以及开发潜在的治疗方法。在此，我们报告了一类通过竞争性 GMDS 抑制直接靶向从头 GDP-岩藻糖生物合成的岩藻糖基化抑制剂。我们证明了细胞通透的氟化鼠李糖 1-磷酸衍生物（Fucotrim I 和 II）是代谢前药，可代谢为其各自的 GDP-甘露糖衍生物，并有效抑制细胞岩藻糖基化。
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