PRODUCTION SYNTHESIS OF INSULIN-LIKE GROWTH FACTOR II SYNTHESIS OF IMPROVED DELIVERY FORMS OF ANTIVIRAL AGENTS

NEW METHODS ARE NEEDED WHICH WILL ALLOW FOR THE ROUTINE PRODUCTION BY SOLID PHASE SYNTHESIS OF PEPTIDES OF 60 TO 70 AMINO ACIDS IN LENGTH ON THE 50 TO 100 GRAM SCALE. CURRENTLY, PEPTIDES CAN BE MADE EITHER BY SOLID PHASE SYNTHESIS TECHNIQUES ON SMALL SCALE (UP TO 5 GM) OR BY GENETIC ENGINEERING: BOTH OF THESE PRODUCTION METHODS ARE COSTLY AND RESULT IN VERY HIGH PRICES FOR COMMERCIALLY AVAILABLE PEPTIDES. THIS PROJECT WILL DEVELOP THE REQUIRED TECHNIQUES FOR THE SOLID PHASE SYNTHESIS OF INSULIN-LIKE GROWTH FACTOR II (IGF-II) BY FRAGMENT ASSEMBLY AND WILL PRODUCE BY THE END OF PHASE II 50 TO 100 GRAMS OF THIS PEPTIDE. THE TECHNIQUES DEVELOPED FOR THE SYNTHESIS OF THIS PEPTIDE GROWTH FACTOR WHICH IS 67 AMINO ACIDS IN LENGTHAND WHICH CONTAINS THREE INTRACHAIN DISULFIDES WILL ALSO BE DIRECTLY APPLICABLE TO OTHER BIOLOGICALLY ACTIVE PEPTIDES, SUCH AS EPIDERMAL GROWTH FACTOR AND TRANSFORMING GROWTH FACTOR-ALPHA. ONLY BY DEVELOPING NEW METHODS AND APPROACHESCAN PEPTIDES OF LONGER LENGTH AND OF GREATER STRUCTURAL COMPLEXITY BE ROUTINELY PRODUCED COMMERCIALLY AT REASONABLE COSTS. THIS PROJECT WILL USE A NEW ACID SENSITIVE SOLID PHASE SUPPORT RESIN DEVELOPED IN A PREVIOUS SBIR CONTRACT TOBUILD THE REQUIRED PROTECTED FRAGMENTS BY FMOC SOLID PHASE PEPTIDE SYNTHESIS. PHASE I WILL FOCUS ON THE SMALL SCALE PRODUCTION OF IGF-II BY FRAGMENT ASSEMBLY. THE PROBLEMS ENCOUNTERED IN THE TREATMENT OF HUMAN HERPES SIMPLEX VIRUS TYPE 1 AND TYPE 2 INFECTIONS HAVE BEEN ATTRIBUTED TO THE INABILITY OF ANTIVIRAL AGENTS TO ATTAIN OPTIMAL CONCENTRATIONS AT THE SITE OF VIRAL INFECTION. TO CIRCUMVENT THESE PROBLEMS UTILIZATION OF THE NOVEL CHEMICAL DELIVERY SYSTEM (ANALOGOUS TO THE NADH NAD(+) REDOXSYSTEM) DEVELOPED BY BODOR AND ASSOCIATES IS PROPOSED. THISSYSTEM IS BASED ON THE INTERCONVERSION OF LIPOPHILIC DIHYDROPYRIDINES WHICH READILY CROSS BBB AND HYDROPHILIC PYRIDINIUM SALTS WHICH ARE "LOCKED" IN THE BRAIN. THE ADVANTAGES OF THIS SYSTEM ARE 1) LOWER PERIPHERAL CONCENTRATIONS OF THE ACTIVE AGENT AND CONSEQUENTLY REDUCED SYSTEMIC TOXICITY 2) GREATER EFFICACY SINCE A LOWER DOSE CANBE GIVEN TO ATTAIN CLINICALLY EFFECTIVE CEREBRAL CONCENTRATIONS. THE SPECIFIC GOAL OF THIS PROPOSAL IS TO APPLY THE CHEMICAL DELIVERY SYSTEM TO SELECTED ANTIHERPETIC AGENTS TO FACILITATE DELIVERY ACROSS BIOLOGICAL MEMBRANES. CONSIDERING THE INCIDENCE AND THE DEVASTATING EFFECTS OF HERPES SIMPLEX INFECTIONS IN HUMANS, THERE IS A NEED FOR NEWINNOVATIVE RESEARCH ESPECIALLY IN THE DEVELOPMENT OF TARGETED ANTIHERPETIC AGENTS THROUGH EFFECTIVE DELIVERY SYSTEMS.