科學家在本月的《自然—化學生物學》Nature Chemical Biology上描述了數(shù)種針對新型酶的細胞滲透抑制劑,。人們通過了解發(fā)育,、細胞運輸、宿主—病原體互作用的方式來探尋疾病背后的生物學基本原理,，而這些酶抑制劑與這種探尋存在關聯(lián),。
尋找能夠穿過細胞膜并在細胞內發(fā)生作用的酶抑制劑仍然是一項有意義的挑戰(zhàn)，尤其是找尋針對那些高帶電碳水化合物酶的抑制劑,。我們現(xiàn)在已經(jīng)知道,，那些能夠控制碳水化合物代謝的細胞酶會允許一些非天然分子進入到正常的代謝通路中；此外,，藥物化學家們長期致力于研究“前體藥物”或分子——可以通過一些手段將其掩飾,，一旦進入體內或細胞內，其又可以發(fā)生變化而被激活,。先前的研究已證明,，將上述兩點結合，可將藥物打造成一種糖類相似物,，從而順利地滲透入細胞內，而后通過若干步驟轉變?yōu)楸患せ畹奶腔D移酶抑制劑,。
James Paulson等人通過研究證明,，利用該法可合成出針對唾液酸轉移酶和海藻糖基轉移酶的抑制劑——這兩種酶能分別將唾液酸和海藻糖這兩種特定糖類基團與一系列生物標的相結合,。由于目前還沒有針對這兩種在細胞內工作的酶合成出小分子的抑制劑，因而這些新合成出的化合物將對今后研究碳水化合物結構與重要的生物學進程之間的聯(lián)系提供直接幫助,。（生物谷Bioon.com）
doi:10.1038/nchembio.999
PMC:
PMID:
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.
