Liu Yanyan, Sweet Igor R, Boons Geert-Jan
Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, United States.
JACS Au. 2024 Sep 23;4(10):3953-3963. doi: 10.1021/jacsau.4c00681. eCollection 2024 Oct 28.
Fucosyl transferases (FUTs) are enzymes that transfer fucose (Fuc) from GDP-Fuc to acceptor substrates, resulting in fucosylated glycoconjugates that are involved in myriad physiological and disease processes. Previously, it has been shown that per--acetylated 2-F-Fuc can be taken up by cells and converted into GDP-2-F-Fuc, which is a competitive inhibitor of FUTs. Furthermore, it can act as a feedback inhibitor of biosynthesis of GDP-Fuc resulting in reduced glycoconjugate fucosylation. However, GDP-2-F-Fuc and several other reported analogues are slow substrates, which can result in unintended incorporation of unnatural fucosides. Here, we describe the design, synthesis, and biological evaluation of GDP-2,2-di-F-Fuc and the corresponding prodrugs as an inhibitor of FUTs. This compound lacks the slow transfer activity observed for the monofluorinated counterpart. Furthermore, it was found that GDP-2-F-Fuc and GDP-2,2-di-F-Fuc have similar values for the various human fucosyl transferases, while the corresponding phosphate prodrugs exhibit substantial differences in inhibition of cell surface fucosylation. Quantitative sugar nucleotide analysis by Liquid chromatography-mass spectrometry (LC-MS) indicates that the 2,2-di-F-Fuc prodrug has substantially greater feedback inhibitory activity. It was also found that by controlling the concentration of the inhibitor, varying degrees of inhibition of the biosynthesis of different types of fucosylated glycan structures can be achieved. These findings open new avenues for the modulation of fucosylation of cell surface glycoconjugates.
岩藻糖基转移酶（FUTs）是一类将岩藻糖（Fuc）从GDP - Fuc转移至受体底物的酶，从而产生参与众多生理和疾病过程的岩藻糖基化糖缀合物。此前研究表明，全乙酰化的2 - F - Fuc可被细胞摄取并转化为GDP - 2 - F - Fuc，后者是FUTs的竞争性抑制剂。此外，它还可作为GDP - Fuc生物合成的反馈抑制剂，导致糖缀合物岩藻糖基化减少。然而，GDP - 2 - F - Fuc及其他一些报道的类似物是缓慢底物，这可能导致非天然岩藻糖苷的意外掺入。在此，我们描述了GDP - 2,2 - 二 - F - Fuc及其相应前药作为FUTs抑制剂的设计、合成及生物学评价。该化合物缺乏单氟代类似物所观察到的缓慢转移活性。此外，发现GDP - 2 - F - Fuc和GDP - 2,2 - 二 - F - Fuc对各种人类岩藻糖基转移酶具有相似的值，而相应的磷酸前药在抑制细胞表面岩藻糖基化方面表现出显著差异。通过液相色谱 - 质谱联用（LC - MS）进行的定量糖核苷酸分析表明，2,2 - 二 - F - Fuc前药具有显著更强的反馈抑制活性。还发现通过控制抑制剂的浓度，可以实现对不同类型岩藻糖基化聚糖结构生物合成的不同程度抑制。这些发现为调节细胞表面糖缀合物的岩藻糖基化开辟了新途径。
