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

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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.