Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, People's Republic of China.
J Med Chem. 2012 Mar 8;55(5):2144-53. doi: 10.1021/jm2013503. Epub 2012 Feb 27.
The influenza virus nucleoprotein (NP) is an emerging target for anti-influenza drug development. Nucleozin (1) and its closely related derivatives had been identified as NP inhibitors displaying anti-influenza activity. Utilizing 1 as a lead molecule, we successfully designed and synthesized a series of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents. One of the most potent compounds, 3b, inhibited the replication of various H3N2 and H1N1 influenza A virus strains with IC(50) values ranging from 0.5 to 4.6 μM. Compound 3b also strongly inhibited the replication of H5N1 (RG14), amantidine-resistant A/WSN/33 (H1N1), and oseltamivir-resistant A/WSN/1933 (H1N1, 274Y) virus strains with IC(50) values in sub-μM ranges. Further computational studies and mechanism investigation suggested that 3b might directly target influenza virus A nucleoprotein to inhibit its nuclear accumulation.
流感病毒核蛋白 (NP) 是抗流感药物研发的新兴靶点。核嗪 (1) 及其密切相关的衍生物已被鉴定为具有抗流感活性的 NP 抑制剂。我们利用 1 作为先导化合物，成功设计并合成了一系列 1H-1,2,3-三唑-4-甲酰胺衍生物，作为新型抗甲型流感药物。其中一种最有效的化合物 3b，对各种 H3N2 和 H1N1 流感 A 病毒株的复制具有抑制作用，IC50 值范围为 0.5 到 4.6 μM。化合物 3b 还强烈抑制 H5N1 (RG14)、金刚烷胺耐药 A/WSN/33 (H1N1) 和奥司他韦耐药 A/WSN/1933 (H1N1, 274Y) 病毒株的复制，IC50 值在亚微摩尔范围内。进一步的计算研究和机制研究表明，3b 可能直接靶向流感病毒 A 核蛋白，抑制其核内积累。
