Department of Chemistry, University of Houston, Houston, Texas 77204-5641
Introduction
The influenza hemagglutinin coat glycoprotein is responsible for the
attachment of the virus to the host-cell receptors by binding to a terminal
sialic acid, and also for mediating a membrane fusion event leading to
the release of the viral nucleocapsid into the cytoplasm (Wiley and Skehel,1987).
Hemagglutinin may therefore be a suitable target for the design of anti-influenza
agents which would inhibit its action by binding at a functionally important
region of the molecule.
The influenza virus proteins undergo a high rate of mutation, enabling
the virus to evade the body's immune defense system and giving rise to
periodic epidemics and pandemics of the disease. However, it may be possible
to design an anti-influenza agent that is effective against a wide range
of strains of influenza, regardless of mutation of the virus, by designing
it to bind specifically to a highly conserved region of hemagglutinin.
The three-dimensional structure of hemagglutinin has been solved by
X-ray crystallography (Wilson et al., 1981) and therefore, the method
of receptor fit (Goodford, 1984; Beddell, 1984) may be used in order to
design novel anti-influenza agents targeted against this glycoprotein.
There are four conserved regions in hemagglutinin. Of these, the hostcell
receptor binding pocket appears to be the most appropriate target binding
site for inhibitors designed by the method of receptor fit. Not only is
it of known structure, functionally important, and highly conserved, butit
also satisfies other criteria necessary for the application of this method.
In addition, it has recently been proposed as a suitable site for the binding
of a drug (Weis et a/., 1988).
Therefore, the strategy adopted in this work was to design ligands
which would bind tightly to the host-cell receptor binding site, preventing
the terminal sialic acid of the cell receptors from binding and so preventing
the attachment of influenza viruses to cells and consequent viral infection.
In order to design such ligands, the GRID method (Goodford, 1985; Boobbyer
et al., 1989) was used to determine the type and position of chemical
groups which might bind strongly in the hemagglutinin receptor binding
pocket.
In ``Use of X-Ray Crystallography in the Design of Antiviral Agents''
Eds. Laver,G. and Air,G.
Academic Press, Inc., San Diego (1990) pp61-74