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UK researchers have determined the X-ray structure of a key protein of the avian influenza virus that reveals a peculiarity that might prove the Achilles' heel of bird flu and allow new potent drugs against the disease that could stave off a flu pandemic. H5N1 virus is named for the particular haemagglutinin (H) and neuraminidase (N) proteins that are found on the viral coat. Haemagglutinin allows the viral particles to bind to and infect host cells, while neuraminidase helps the virus to escape infected cells and attack new ones. There are 16 H's and 9 N's in known variants on the influenza type A virus. It is the neuraminidases that are the target for drugs such as oseltamivir (Tamiflu) and zanamivir (Relenza). The trouble is, N1 is not the exact target for which they were designed. Rather the design of these drugs was based on neuraminidases N2 and N9 found in other influenza type A strains. H5N1 itself resides in a genetically distinct group. Structural information from this group could be critical to producing drugs that are resistant to emerging resistance in influenza. Now, John Skehel and his colleagues at the National Institute of Medical Research, in London, have obtained a structure for the N1 enzyme, which is closely related to the N4 and N8 enzymes, as well as structures of their complexes with the enzyme inhibitors oseltamivir, zanamivir, DANA and peramivir and have shown that these N's are indeed structurally distinct from those to which the current drugs are targeted. The group-1 neuraminidases, the researchers found, have a cavity adjacent to their active sites that closes on binding to the enzyme's substrate. "Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs," the researchers say. The researchers suggest that new drugs effective against group-1 neuraminidases might be constructed by adding different groups to the skeletons of existing inhibitors. "An effective group-specific inhibitor could be of considerable value against the currently circulating human H1N1 viruses, the H3N8 viruses that repeatedly cause influenza in equines and are now causing widespread disease in canines, and the avian H5N1 viruses that currently threaten the human population," the researchers explain. Related links:
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Sir John Skehel, another distinction |
