Selective Inhibitors of Human Neuraminidase 1 (NEU1)
Selective Inhibitors of Human Neuraminidase 1 (NEU1)
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DOI：
10.1021/acs.jmedchem.8b04111
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发表时间：
2018-12-27
影响因子：
7.3
通讯作者：
Cairo, Christopher W.
中科院分区：
文献类型：
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作者：
Guo, Tianlin;Heon-Roberts, Rachel;Cairo, Christopher W.
人神经氨酸酶（NEU）抑制剂被认为是研究NEU生物学功能的重要工具，并且将是阐明这些酶在调节细胞聚糖库中的作用的有力工具。在这里，我们报告的人神经氨酸酶1（NEU 1）和神经氨酸酶2（NEU 2）酶的选择性抑制剂具有特殊效力的发现。合成了修饰的2-脱氧-2，3-二脱氢-N-乙酰神经氨酸（DANA）类似物（在C5-或C9-位置具有变异性）的文库，并针对四种人神经氨酸酶同工酶（NEU 1 -4）进行了评价。在C5和C9位置处具有酰胺接头的疏水基团被NEU 1很好地容纳，并且发现己酰胺基在两个位置处给出最佳效力。虽然CS-己酰胺基-C9-己酰胺基-DANA类似物对于组合修饰没有显示出协同改进，但是在单个位置处的延长的烷基酰胺与在第二个位置处的较小基团组合得到增加的效力。鉴定的最佳NEU 1抑制剂是C5-己酰胺基-C9-乙酰胺基-DANA，其Ki为53 +/- 5 nM，选择性是其他同工酶的340倍。此外，我们证明，C5-修饰与C4-胍基组合提供了报道的最有效的NEU 2抑制剂，Ki为1.3 +/- 0.2 μ M，选择性是其他NEU同工酶的7倍。
Inhibitors of human neuraminidase enzymes (NEU) are recognized as important tools for the study of the biological functions of NEU and will be potent tools for elucidating the role of these enzymes in regulating the repertoire of cellular glycans. Here we report the discovery of selective inhibitors of the human neuraminidase 1 (NEU1) and neuraminidase 2 (NEU2) enzymes with exceptional potency. A library of modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) analogues, with variability in the C5- or C9-position, were synthesized and evaluated against four human neuraminidase isoenyzmes (NEU1-4). Hydrophobic groups with an amide linker at the C5 and C9 positions were well accommodated by NEU1, and a hexanamido group was found to give the best potency at both positions. While the CS-hexanamido-C9-hexanamido-DANA analogue did not show synergistic improvements for combined modification, an extended alkylamide at an individual position combined with a smaller group at the second gave increased potency. The best NEU1 inhibitor identified was a C5-hexanamido-C9-acetamido-DANA that had a K-i of 53 +/- 5 nM and 340-fold selectivity over other isoenzymes. Additionally, we demonstrated that C5-modifications combined with a C4-guandino group provided the most potent NEU2 inhibitor reported, with a K-i of 1.3 +/- 0.2 mu M and 7-fold selectivity over other NEU isoenzymes.