DEVELOPMENT OF INTERLEUKIN-6 ANTAGONISTS

THE LONG-TERM OBJECTIVE IS TO DEVELOP PEPTIDE-BASED INTERLEUKIN-6 (IL-6)-SPECIFIC INHIBITORS FOR THE TREATMENT OF DISEASES IN WHICH IL-6 MIGHT CONTRIBUTE TO THE PATHOGENESIS. PEPTIDES WITH IL-6 ANTAGONIST ACTIVITY IN VITRO WILL THEN BE TESTED IN ANIMAL MODELS FOR EFFICACY. BECAUSE METABOLIC STABILITY MAY BE A CONCERN WHEN PEPTIDES ARE ADMINISTERED IN VIVO, AN ANALOG PROGRAM WILL BE INITIATED TO MODIFY THE MOST ACTIVE PEPTIDES TO MAXIMIZE THEIR ACTIVITY. IF THESE ATTEMPTS ARE SUCCESSFUL, ADDITIONAL PEPTIDOMIMETICSWILL BE DESIGNED, LEADING TO ORALLY ACTIVE COMPOUNDS. PRINCIPLES ESTABLISHED IN THIS PROJECT COULD PROVIDE USEFUL INFORMATION FOR THE DESIGN OF A NEW CLASS OF PHARMACEUTICAL COMPOUNDS FOR SELECTIVE MANIPULATION OF THE IMMUNE SYSTEM. SHORT SEQUENCES OF 10 TO 15 AMINO ACIDS THAT ARE CRUCIAL FORLIGAND-RECEPTOR INTERACTION OF IL-6 WILL BE IDENTIFIED, SYNETHSIZED BY SOLID-PHASE SYNTHESIS, AND TESTED FOR IL-6 ANTAGONIST ACTIVITY IN IL-6-SPECIFIC BIOASSAYS. THE HYPOTHESIS THAT STRUCTURAL PREDICTION MAY HELP IDENTIFY RECEPTOR-LIGAND INTERACTION SITES WILL BE TESTED, AND ANALOGS OF ACTIVE PEPTIDES WILL BE SYNTHESIZED TO IDENTIFY THE OPTIMUM EPITOPE AND ITS MINIMAL STRUCTURAL REQUIREMENTS. POLYCLONAL ANTIPEPTIDE ANTIBODIES WILL BE GENERATED FOR FURTHER CHARACTERIZATION OF THE EPITOPES OF INTEREST.