A recently developed computer algorithm, capable of defining the accessible surface of polypeptides, has revealed a possible binding site on the hemagglutinin (HA) envelope protein of influenza virus. The proximity of this site to the fusion peptide of HA makes it an attractive candidate as a target for arresting influenza by inhibiting virus membrane fusion. A variety of structures, complementary in shape and charge to this HA site, have been identified by computer docking experiments. Deoxycytidine, and adamantane skeletons provide the best fits for compounds which are readily synthesized. The proposal describes the acquisition of commercially available compounds and the synthesis of four new trial ligands as representatives of these structures to test the feasibility of preventing membrane fusion of influenza virus by binding to this HA site. Trial ligands that inhibit release of the fusion peptide from the HA trimer interface, and show in vitro inhibition of viral fusion, will be tested for antiviral activity by plaque assay. This Phase I feasibility study will provide a framework leading to the development of low dosage, safe anti- influenza therapeutics in Phase II. This work will also provide a new strategy for antiviral therapy.
