An Approach to the Design of Anti-Influenza, Agents

Rebecca C. Wade

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


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