科学家在本月的《自然—化学生物学》Nature Chemical Biology上描述了数种针对新型酶的细胞渗透抑制剂。人们通过了解发育、细胞运输、宿主—病原体互作用的方式来探寻疾病背后的生物学基本原理，而这些酶抑制剂与这种探寻存在关联。
寻找能够穿过细胞膜并在细胞内发生作用的酶抑制剂仍然是一项有意义的挑战，尤其是找寻针对那些高带电碳水化合物酶的抑制剂。我们现在已经知道，那些能够控制碳水化合物代谢的细胞酶会允许一些非天然分子进入到正常的代谢通路中；此外，药物化学家们长期致力于研究“前体药物”或分子——可以通过一些手段将其掩饰，一旦进入体内或细胞内，其又可以发生变化而被激活。先前的研究已证明，将上述两点结合，可将药物打造成一种糖类相似物，从而顺利地渗透入细胞内，而后通过若干步骤转变为被激活的糖基转移酶抑制剂。
James Paulson等人通过研究证明，利用该法可合成出针对唾液酸转移酶和海藻糖基转移酶的抑制剂——这两种酶能分别将唾液酸和海藻糖这两种特定糖类基团与一系列生物标的相结合。由于目前还没有针对这两种在细胞内工作的酶合成出小分子的抑制剂，因而这些新合成出的化合物将对今后研究碳水化合物结构与重要的生物学进程之间的联系提供直接帮助。（生物谷Bioon.com）
doi:10.1038/nchembio.999
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Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome
Cory D Rillahan, Aristotelis Antonopoulos, Craig T Lefort, Roberto Sonon, Parastoo Azadi, Klaus Ley, Anne Dell, Stuart M Haslam & James C Paulson
Despite the fundamental roles of sialyl- and fucosyltransferases in mammalian physiology, there are few pharmacological tools to manipulate their function in a cellular setting. Although fluorinated analogs of the donor substrates are well-established transition state inhibitors of these enzymes, they are not membrane permeable. By exploiting promiscuous monosaccharide salvage pathways, we show that fluorinated analogs of sialic acid and fucose can be taken up and metabolized to the desired donor substrate–based inhibitors inside the cell. Because of the existence of metabolic feedback loops, they also act to prevent the de novo synthesis of the natural substrates, resulting in a global, family-wide shutdown of sialyl- and/or fucosyltransferases and remodeling of cell-surface glycans. As an example of the functional consequences, the inhibitors substantially reduce expression of the sialylated and fucosylated ligand sialyl Lewis X on myeloid cells, resulting in loss of selectin binding and impaired leukocyte rolling.
