We propose collaborative experiments that combine organic syntheses, X-ray crystallography, and computational chemistry, all aimed at developing an understanding of molecular structures as a basis for the development of antiviral therapies. We plan to test whether inhibiting influenza virus infection can be accomplished by blocking the binding of the virus to its cellular receptor and/or the inhibition of viral entry by blocking the virus's membrane fusion mechanism. We propose to use three-dimensional structure of the virus surface protein (HA) responsible for these activities (receptor binding and membrane fusion) and the structures of complexes of this protein with receptor analogs as a starting point for designing and testing inhibitors. We plan to develop computational methods and to determine other structures to assist the design process. We will explore increasing the affinity of ligands, matching bivalent ligands to the virus surface lattice, and interfering with necessary conformational changes by stabilizing the membrane-fusion-inactive conformation. Our goal is to develop a structural foundation for antiviral drug design.
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