New Small Molecule Entry Inhibitors Targeting Hemagglutinin-Mediated Influenza A Virus Fusion
New Small Molecule Entry Inhibitors Targeting Hemagglutinin-Mediated Influenza A Virus Fusion
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DOI：
10.1128/jvi.01225-13
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发表时间：
2014-02-01
影响因子：
5.4
通讯作者：
Bowlin, Terry L.
中科院分区：
文献类型：
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作者：
Basu, Arnab;Antanasijevic, Aleksandar;Bowlin, Terry L.
流感病毒是世界范围内的主要公共卫生威胁，由于出现耐药病毒株，抗病毒治疗的选择受到限制。流感病毒糖蛋白血凝素（HA）在病毒感染的早期阶段发挥着关键作用，包括受体结合和膜融合，使其成为开发抗流感药物的潜在靶点。利用基于伪病毒的高通量筛选，我们已经确定了几种能够抑制流感病毒进入的新小分子。我们优先选择了两种新型抑制剂MBX2329和MBX2546，它们分别以氨基烷基酚醚和磺胺为支架，特异性抑制ha介导的病毒进入。这两种化合物(i)是有效的（50%抑制浓度[IC50] 0.3至5.9 μ M）；（ii）具有选择性（50%细胞毒性浓度[CC50] > 100 μ M），对不同流感病毒株的选择性指数（SI）值为> 20 ~ 200；（三）抑制多种甲型流感病毒，包括2009年大流行性流感病毒a /H1N1/2009、高致病性禽流感病毒a /H5N1和对奥司他韦具有耐药性的a /H1N1毒株；（iv）与奥司他韦表现出大量协同作用（36和331 μ M-2 %， 95%置信水平）；(v)具有化学上易于处理的结构。作用机制研究表明MBX2329和MBX2546都以不重叠的方式与HA结合。HA介导的鸡红细胞（crbc）溶血、单克隆抗体（MAb） C179竞争分析和突变分析的其他结果表明，这些化合物结合在HA三聚体的茎区，抑制HA介导的融合。因此，MBX2329和MBX2546代表了化学优化的新起点，并有可能为研究ha介导的进入过程提供有价值的未来治疗选择和研究工具。
Influenza viruses are a major public health threat worldwide, and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. Using pseudotype virus-based high-throughput screens, we have identified several new small molecules capable of inhibiting influenza virus entry. We prioritized two novel inhibitors, MBX2329 and MBX2546, with aminoalkyl phenol ether and sulfonamide scaffolds, respectively, that specifically inhibit HA-mediated viral entry. The two compounds (i) are potent (50% inhibitory concentration [IC50] of 0.3 to 5.9 mu M); (ii) are selective (50% cytotoxicity concentration [CC50] of> 100 mu M), with selectivity index (SI) values of> 20 to 200 for different influenza virus strains; (iii) inhibit a wide spectrum of influenza A viruses, which includes the 2009 pandemic influenza virus A/H1N1/2009, highly pathogenic avian influenza (HPAI) virus A/H5N1, and oseltamivir-resistant A/H1N1 strains; (iv) exhibit large volumes of synergy with oseltamivir (36 and 331 mu M-2 % at 95% confidence); and (v) have chemically tractable structures. Mechanism-of-action studies suggest that both MBX2329 and MBX2546 bind to HA in a nonoverlapping manner. Additional results from HA-mediated hemolysis of chicken red blood cells (cRBCs), competition assays with monoclonal antibody (MAb) C179, and mutational analysis suggest that the compounds bind in the stem region of the HA trimer and inhibit HA-mediated fusion. Therefore, MBX2329 and MBX2546 represent new starting points for chemical optimization and have the potential to provide valuable future therapeutic options and research tools to study the HA-mediated entry process.