DESIGN AND ANTIVIRAL PROPERTIES OF INFLUENZA-VIRUS NEURAMINIDASE INHIBITORS

During the infection cycle of influenza virus, progeny virions bud from the plasma membrane of infected cells. At that point they are potentially immobilised because of interactions between the viral haemagglutinin and sialic acid which is found in glycoconjugates on the cell surface and on glycoproteins of the virus itself. Neuraminidase inhibitors might therefore be expected to have an antiviral action by slowing release and subsequently reducing the viral burden in infected hosts. The three-dimensional structure of the influenza virus neuraminidase has been determined by X-ray crystallography to high resolution. The structure demonstrates that strain variation has not yet been observed to include active site residues. Studies of the structure of complexes between the substrate and substrate analogues with the enzyme reveal the method of enzyme-substrate interaction. The structure of the enzyme active site has been used to direct the design of new inhibitors of the enzyme. These inhibitors block multi-cycle replication of virus in tissue culture and have antiviral properties in animal models.