Functions of surface glycoproteins of myxoviruses and paramyxoviruses and their inhibition.

Two glycoproteins, HN and F, are present on the surface of paramyxoviruses. HN has receptor-binding amd neuraminidase activities. F is involved in viral penetration, cell fusion and haemolysis and is activated by proteolytic cleavage by a host enzyme into two disulphide-bonded subunits (f1 and F2). The ability of the virus to initiate infection and undergo multiple cycle replication depends on the presence of an activating protease in the host; thus cleavage of F is a major determinant of pathogenesis. The new N-terminus generated on F1 by cleavage is involved in biological activity, and the amino acid sequence of this region of F1 by cleavage is involved in biological activity, and the amino acid sequence of this region of F1 is hydrophobic and highly conserved among para-myxoviruses. In an attempt to design specific inhibitors, oligopeptides and analogous to this region were synthesized and found to be highly active, specific inhibitors of viral penetration, cell fusion and haemolysis. Inhibition is amino-acid-sequence-specific and affected by peptide length, steric configuration and addition of groups to the n-terminal and C-terminal amino acids. Replication of influenza virus was also specifically inhibited by oligopeptides resembling the N-terminus of the HA2 polypeptide. Like that of F1 protein the N-terminus of HA2 is generated by a proteolytic cleavage that activates infectivity. These results have provided information on the action of proteins in viral penetration and membrane fusion and they suggest a possible new approach to chemical inhibition of viral replication. Studies with specific antibodies to each of the paramyxovirus glycoproteins have shown that antibodies to the F protein are essential for effective prevention of the spread of infection. Antibodies to the HN protein, although capable of neutralizing released virus, do not prevent spread to adjacent cells through membrane fusion mediated by the F protein. These findings have implications for the design of effective vaccines against paramyxoviruses and also provided additional insight into the mechanisms involved in the atypical and severe infections observed in individuals who received inactivated paramyxovirus vaccines and were later infected.