ANTI-FUSOGENIC ANTIVIRALS: DESIGN AND TESTING

A RECENTLY DEVELOPED COMPUTER ALGORITHM, CAPABLE OF DEFININGTHE ACCESSIBLE SURFACE OF POLYPEPTIDES, HAS REVEALED A POSSIBLE BINDING SITE ON THE HEMAGGLUTININ (HA) ENVELOPE PROTEIN OF INFLUENZA VIRUS. A VARIETY OF STRUCTURES, COMPLEMENTARY IN SHAPE AND CHARGE TO THIS HA SITE, HAVE BEEN IDENTIFIED BY COMPUTER DOCKING EXPERIMENTS. THIS PROJECT WILL ACQUIRE COMMERCIALLY AVAILABLE COMPOUNDS AND SYNTHESIZE FOUR NEW TRIAL LIGANDS TO TEST THE FEASIBILITY OF PREVENTING MEMBRANE FUSION OF INFLUENZA VIRUS BY BINDING TO THIS HA SITE. TRIAL LIGANDS THAT INHABIT 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.