Influenza A viruses (IAVs) cause seasonal flu and occasionally pandemics. The current therapeutics against IAVs target two viral proteins - neuraminidase (NA) and M2 ion-channel protein. However, M2 ion channel inhibitors (amantadine and rimantadine) are no longer recommended by CDC for use due to the emergence of high level of antiviral resistance among the circulating influenza viruses, and resistant strains to NA inhibitors (oseltamivir and zanamivir) have also been reported. Therefore, development of novel anti-influenza therapies is urgently needed. As one of the viral surface glycoproteins, hemagglutinin (HA) mediates critical virus entry steps including virus binding to host cells and virus-host membrane fusion, which makes it a potential target for anti-influenza drug development. In this study, we report the identification of compound CBS1116 with a 4-aminopiperidine scaffold from a chemical library screen as an entry inhibitor specifically targeting two group 1 influenza A viruses, A/Puerto Rico/8/34 (H1N1) and recombinant low pathogenic avian H5N1 virus (A/Vietnam/1203/04, VN04Low). Mechanism of action studies show that CBS1116 interferes with the HA-mediated fusion process. Further structure activity relationship study generated a more potent compound CBS1117 which has a 50% inhibitory concentration of 70 nM and a selectivity index of ~4000 against A/Puerto Rico/8/34 (H1N1) infection in human lung epithelial cell line (A549).

中文翻译：

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用4-氨基哌啶支架靶向A组流感1病毒鉴定进入抑制剂。

甲型流感病毒（IAV）引起季节性流感，并偶尔引起大流行。目前针对IAV的疗法靶向两种病毒蛋白-神经氨酸酶（NA）和M2离子通道蛋白。但是，由于正在流行的流感病毒中出现了高水平的抗病毒耐药性，CDC不再推荐使用M2离子通道抑制剂（金刚烷胺和金刚乙胺），并且还报道了对NA抑制剂（oseltamivir和zanamivir）具有耐药性的菌株。 。因此，迫切需要开发新颖的抗流感疗法。作为病毒表面糖蛋白之一，血凝素（HA）介导关键的病毒进入步骤，包括病毒与宿主细胞结合和病毒-宿主膜融合，这使其成为抗流感药物开发的潜在目标。在这个研究中，我们报道了从化学文库筛选中鉴定出具有4-氨基哌啶骨架的化合物CBS1116作为进入抑制剂的作用，该进入抑制剂专门针对两种1型甲型流感病毒，A /波多黎各/ 8/34（H1N1）和重组低致病性禽H5N1病毒（ A /越南/ 1203/04，VN04低）。作用机理研究表明，CBS1116干扰了HA介导的融合过程。进一步的结构活性关系研究产生了更有效的化合物CBS1117，其对人肺上皮细胞系（A549）的A /波多黎各/ 8/34（H1N1）感染具有50％的抑制浓度和〜4000的选择性指数。 。A /波多黎各Rico / 8/34（H1N1）和重组的低致病性禽H5N1病毒（A / Vietnam / 1203/04，VN04Low）。作用机理研究表明，CBS1116干扰了HA介导的融合过程。进一步的结构活性关系研究产生了更有效的化合物CBS1117，其对人肺上皮细胞系（A549）的A /波多黎各/ 8/34（H1N1）感染具有50％的抑制浓度和〜4000的选择性指数。 。A /波多黎各Rico / 8/34（H1N1）和重组的低致病性禽H5N1病毒（A / Vietnam / 1203/04，VN04Low）。作用机理研究表明，CBS1116干扰了HA介导的融合过程。进一步的结构活性关系研究产生了更有效的化合物CBS1117，其对人肺上皮细胞系（A549）的A /波多黎各/ 8/34（H1N1）感染具有50％的抑制浓度和〜4000的选择性指数。 。