Identification of novel inhibitory compounds of the surface glycoproteins of Influenza viruses using fragment screening

流感病毒流行每年在全世界造成数十万人死亡。偶尔，一种新的病毒开始传播，导致一场大流行，导致数千万人死亡。上个世纪有三次大流行，每一次都是由一种不同类型的流感病毒引起的；1918年的H1N1、1957年的H2N1和1968年的H3N2.流感病毒表面有血凝素(H)和神经氨酸酶(N)两种蛋白，H有16个亚型(H1-H16)，N有9个亚型(N1-N9)。所有的组合在鸟类种群中都是自然存在的。自2003年以来，一种高致病性H5N1禽流感病毒已造成140多人死亡，并有可能引发下一次大流行。目前，有两种获得临床许可的抗流感药物(达菲和瑞沙)，这两种药物都是通过了解N蛋白的三维结构而设计的。尽管及时给药有效，但已经出现了对这些药物具有抗药性的变异病毒。因此，迫切需要开发抗流感病毒的新型药物。我们最近从一种感染了越南人的H5N1病毒中阐明了N1的三维结构。令人惊讶的是，该结构在达菲和瑞乐沙的结合部位附近的N1蛋白中显示了一个新的口袋。我们建议利用这种结构的知识来设计新型的抗流感药物。

Influenza virus epidemics are responsible for hundreds of thousands of deaths worldwide per year. Occasionally, a new virus starts to circulate which causes a pandemic resulting in ten of millions of deaths. There were three pandemics in the last century, each caused by a different type of Influenza virus; H1N1 in 1918, H2N2 in 1957 and H3N2 in 1968. Influenza viruses have two proteins on their surface, Haemagglutinin (H) and Neuraminidase (N), and there are 16 subtypes of H (H1-H16) and 9 subtypes of N (N1-N9). All combinations are found naturally in the bird population. Since 2003, a highly pathogenic avian H5N1 virus has caused in excess of 140 human deaths and threatens to cause the next pandemic. At present, there are two clinically licensed anti-Influenza drugs (Tamiflu and Relenza) and both of these were designed through knowledge of the three-dimensional structure of the N protein. Although effective upon prompt administration, mutant viruses have arisen that are resistant to these drugs. Therefore, there is an urgent need to develop novel drugs against Influenza viruses. We have recently elucidated the three-dimensional structure of N1 from a H5N1 virus that infected a person in Vietnam. Surprisingly, the structure revealed a novel pocket in the N1 protein next to the binding site of Tamiflu and Relenza. We propose to use the knowledge of this structure to design novel anti-Influenza drugs.