Development of orally active inhibitors of protein and cellular fucosylation
Development of orally active inhibitors of protein and cellular fucosylation
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DOI：
10.1073/pnas.1222263110
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发表时间：
2013-04-02
影响因子：
11.1
通讯作者：
Senter, Peter D.
中科院分区：
文献类型：
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作者：
Okeley, Nicole M.;Alley, Stephen C.;Senter, Peter D.
岩藻糖在糖蛋白和细胞功能中所起的关键作用促使人们进行了大量研究，以确定用于阻断其掺入蛋白质和膜结构的重组和生化策略。围绕工程细胞系的技术已经发展用于抑制体外岩藻糖基化，但它们不适用于体内使用和药物开发。为了解决这个问题，我们筛选了一组岩藻糖类似物，并鉴定了2-氟岩藻糖和5-炔基岩藻糖衍生物，这些衍生物消耗了细胞中的GDP岩藻糖，岩藻糖基转移酶使用的底物将岩藻糖掺入蛋白质和细胞聚糖中。抑制剂在体外用于产生具有增强的抗体依赖性细胞毒性活性的岩藻糖缺陷型抗体。小鼠经口给药时，2-氟岩藻糖可抑制内源性抗体、肿瘤异种移植膜和中性粒细胞粘附聚糖的岩藻糖基化。我们表明，口服2-氟岩藻糖治疗提供了完整的保护，从肿瘤移植在同基因肿瘤疫苗模型，抑制中性粒细胞外渗，并延迟肿瘤异种移植物在免疫缺陷小鼠的生长。这些结果指出了选择性阻断岩藻糖基化聚糖结构内源性产生的分子的几种潜在治疗应用。
The key role played by fucose in glycoprotein and cellular function has prompted significant research toward identifying recombinant and biochemical strategies for blocking its incorporation into proteins and membrane structures. Technologies surrounding engineered cell lines have evolved for the inhibition of in vitro fucosylation, but they are not applicable for in vivo use and drug development. To address this, we screened a panel of fucose analogues and identified 2-fluorofucose and 5-alkynylfucose derivatives that depleted cells of GDPfucose, the substrate used by fucosyltransferases to incorporate fucose into protein and cellular glycans. The inhibitors were used in vitro to generate fucose-deficient antibodies with enhanced antibody-dependent cellular cytotoxicity activities. When given orally to mice, 2-fluorofucose inhibited fucosylation of endogenously produced antibodies, tumor xenograft membranes, and neutrophil adhesion glycans. We show that oral 2-fluorofucose treatment afforded complete protection from tumor engraftment in a syngeneic tumor vaccine model, inhibited neutrophil extravasation, and delayed the outgrowth of tumor xenografts in immune-deficient mice. The results point to several potential therapeutic applications for molecules that selectively block the endogenous generation of fucosylated glycan structures.