Albohy Amgad, Zhang Yi, Smutova Victoria, Pshezhetsky Alexey V, Cairo Christopher W
Alberta Glycomics Center, Department of Chemistry, University of Alberta , Edmonton Alberta T6G 2G2, Canada.
Division of Medical Genetics, Centre Hospitaliere Universitaire Sainte-Justine, University of Montreal , Montreal, Quebec, Canada, and Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University , Montreal, Quebec, Canada.
ACS Med Chem Lett. 2013 May 7;4(6):532-7. doi: 10.1021/ml400080t. eCollection 2013 Jun 13.
The human neuraminidase enzymes (hNEU) play important roles in human physiology and pathology. The lack of potent and selective inhibitors toward these enzymes has limited our understanding of their function and the development of therapeutic applications. Here we report the evaluation of a panel of compounds against the four human neuraminidase isoenzymes. Among the compounds tested, we identified the first selective, nanomolar inhibitors of the human neuraminidase 4 enzyme (NEU4). The most potent NEU4 inhibitor (5-acetamido-9-[4-hydroxymethyl[1,2,3]triazol-1-yl]-2,3,5,9-tetradeoxy-d-glycero-d-galacto-2-nonulopyranosonic acid) was found to have an inhibitory constant (K i ) of 30 ± 19 nM and was 500-fold selective for its target over the other hNEU isoenzymes tested in vitro (NEU1, NEU2, and NEU3). This is the first report of any inhibitor of hNEU with nanomolar potency, and this confirms that the 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) scaffold can be exploited to develop new, potent, and selective inhibitors that target this important family of human enzymes.
人类神经氨酸酶（hNEU）在人体生理和病理过程中发挥着重要作用。缺乏针对这些酶的强效且选择性的抑制剂限制了我们对其功能的了解以及治疗应用的开发。在此，我们报告了一组化合物针对四种人类神经氨酸酶同工酶的评估情况。在测试的化合物中，我们鉴定出了首例对人类神经氨酸酶4（NEU4）具有选择性的纳摩尔级抑制剂。发现最有效的NEU4抑制剂（5-乙酰氨基-9-[4-羟甲基[1,2,3]三唑-1-基]-2,3,5,9-四脱氧-D-甘油-D-半乳糖-2-壬糖醛酸）的抑制常数（Ki）为30±19 nM，并且在体外对其靶标的选择性是所测试的其他hNEU同工酶（NEU1、NEU2和NEU3）的500倍。这是关于具有纳摩尔效力的hNEU抑制剂的首次报道，这证实了2,3-二脱氢-2-脱氧-N-乙酰神经氨酸（DANA）骨架可用于开发针对这一重要人类酶家族的新型、强效且选择性的抑制剂。
