Department of Advanced Transdisciplinary Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
Bioorg Med Chem Lett. 2010 Jun 15;20(12):3772-6. doi: 10.1016/j.bmcl.2010.04.060. Epub 2010 Apr 18.
We designed and synthesized novel trivalent anti-influenza reagents. Sialyllactose was located at the terminal of each valence which aimed to block each receptor-binding site of the hemagglutinin (HA) trimer on the surface of the virus. Structural analyses were carried out with a model which was constructed with a computer simulation. A previously reported cyclic glycopeptide blocker [Ohta, T.; Miura, N.; Fujitani, N.; Nakajima, F.; Niikura, K.; Sadamoto, R.; Guo, C.-T.; Suzuki, T.; Suzuki, Y.; Monde, K.; Nishimura, S.-I. Angew. Chem. Int. Ed., 2003, 42, 5186] bound to the HA in the model. The analyses suggest that the glutamine residue in the cyclic peptide bearing Neu5Acalpha2,3Galbeta1,4Glc trisaccharide via a linker interacts with the Gln189 in HA through hydrogen bonding. The present anti-influenza reagents likely interact with a glutamine residue included in the vicinity of Gln189. A plague reduction assay of the influenza virus, A/PR/8/1934 (H1N1), was performed in MDCK cells to evaluate for the synthesized compounds to inhibit viral replication. One of the compounds showed approximately 85% inhibition at the concentration of 400 microM at 4 degrees C.
我们设计并合成了新型三价抗流感试剂。唾液乳糖位于每个价态的末端，旨在阻断病毒表面血凝素 (HA) 三聚体的每个受体结合位点。结构分析是使用计算机模拟构建的模型进行的。以前报道的环状糖肽抑制剂 [Ohta, T.; Miura, N.; Fujitani, N.; Nakajima, F.; Niikura, K.; Sadamoto, R.; Guo, C.-T.; Suzuki, T.; Suzuki, Y.; Monde, K.; Nishimura, S.-I. Angew. Chem. Int. Ed., 2003, 42, 5186] 在模型中与 HA 结合。分析表明，通过连接子携带 Neu5Acalpha2,3Galbeta1,4Glc 三糖的环状肽中的谷氨酰胺残基通过氢键与 HA 中的 Gln189 相互作用。目前的抗流感试剂可能与 Gln189 附近包含的谷氨酰胺残基相互作用。在 MDCK 细胞中进行了流感病毒 A/PR/8/1934（H1N1）的噬斑减少测定，以评估合成化合物对抑制病毒复制的作用。在 4°C 时，浓度为 400 μM 时，一种化合物的抑制率约为 85%。
