DEVELOPMENT OF METHODS FOR LARGE-SCALE PEPTIDE SYNTHESIS

NEW METHODS ARE NEEDED FOR THE ROUTINE PRODUCTION OF PEPTIDES BY SOLID-PHASE SYNTHESIS ON THE KILOGRAM SCALE. CURRENTLY, PEPTIDES ARE MANUFACTURED ON THE MILLIGRAM TO GRAM SCALE, BUT THIS SMALL-SCALE PRODUCTION RESULTS IN A VERY HIGH PRICE FOR COMMERCIALLY AVAILABLE SYNTHETIC PEPTIDES. THIS PROJECT WILL DEVELOP THE REQUIRED MATERIALS,REAGENTS, AND TECHNIQUES FOR THE LARGE-SCALE (0.4-MOLE) SOLID-PHASE SYNTHESIS OF RAT ATRIAL NATRIURETIC PEPTIDE (ANP), THE RECENTLY DISCOVERED HORMONE PRODUCED BY THE HEART. THE METHODS AND REAGENTS DEVELOPED FOR THE LARGE-SCALE SYNTHESIS OF THIS POLYPEPTIDE HORMONE WILL ALSO BE DIRECTLY APPLICABLE TO OTHER BIOLOGICALLY ACTIVE PEPTIDES. INCREASING THE SIZE OF EACH BATCH IS THE ONLY WAY BY WHICH THE COST OF SYNTHETIC PEPTIDES CAN BE LOWERED. THIS PROJECT WILL DEVELOP THE MATERIALS AND PROCEDURES REQUIRED FOR THE ROUTINE PRODUCTION OF SYNTHETIC PEPTIDES ON THE KILOGRAM SCALE. PHASE I WILL FOCUS ON THE DEVELOPMENT OF THE NEEDED SOLID SUPPORT, PREPARATION OF THE PROTECTED AMINO ACID THAT IS TO BE USED TO DERIVATIZE THE RESIN SUPPORT, AND DERIVATIZATION OF THE RESIN WITH THE PROTECTED AMINO ACID THAT WILL ULTIMATELY BE THE CARBOXYL TERMINAL RESIDUE OF THE FINISHED PEPTIDE.