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. Influenza viruses remain a threat to public health because of their capacity to vary. Immunity to a particular strain, which develops during the course of an infection, is limited to that strain and its very close relatives. The development of drugs which are effective against the virus has proven difficult, partly because of the rapid emergence of resistant strains. Resistance to both drugs and antibodies has as its basis the high error frequency of the viral polymerase. This causes variants to be continuously generated, and when their viability is enhanced, either through the use of drugs or the presence of antibodies in the host, they dominate the population. This paper reviews studies of one of the membrane glyoproteins of the virus which have led to the discovery of a new class of antiviral agent which appears to have broad spectrum activity against type A and B influenza viruses. Influenza is an enveloped virus and two glycoproteins are displayed on the viral envelope (reviewed in (l)), a haemagglutinin and a neuraminidase (sialidase). The receptor for influenza viruses is carbohydrate. Sialic acid (N-acetyl neuraminic acid, NeuSAc, Fig. 1) is the critical sugar residue which interacts weakly with the viral haemagglutinin to cause attachment of virus to target cells. After infection and replication, progeny virions bud at the plasma membrane of the infected cell. A role of the neuraminidase is to facilitate their release to infect other cells. The enzymatic activity of neuraminidase is illustrated in Fig. 1. The enzyme cleaves an a2,3 linkage between NeuSAc and a neighbouring sugar, usually galactose (2-4). An a2,6 linkage is also cleaved by the viral enzyme, although less efficiently, and specificity for the aglycon is weak. This activity destroys the receptors for the viral haemagglutinin which are present on the surface of the infected cell and also on the oligosaccharide side chains of the newly synthesised haemagglutinin and neuraminidase polypeptides within the progeny virion envelope (5,6).