Synthesis of cyclic peptide pharmaceuticals at infinite dilution conditions via oxidative macrocyclization

Cyclic peptides containing disulfide bonds are an essential class of compounds. Of the approximately 60 peptide therapeutics available on the market, many contain cyclic disulfide peptides, such as desmopressin, terlipressin, atosiban, selepressin, oxytocin, and other derivatives. Current methods for cyclization of peptides via disulfide bond formation include in-solution strategies in a liquid state or on-resin strategies in a solid state. However, many of the existing methods have limitations, including low yields and complicated reaction mixtures due to the use of highly reactive oxidizing agents. This project aims to find a good method for cyclizing peptides at an “infinite dilution” condition, which would result in a high cyclization yield with minimal impurities. Cyclic peptides were synthesized using a solid-phase synthesizer and cyclized via sonication with triethylamine in dimethylformamide. We verified that cyclic peptides with a disulfide bond were successfully cyclized with minimal impurities using mass spectroscopy and high-performance liquid chromatography. Applications of this novel on-resin cyclization method include the synthesis of complex cyclic peptides that contain disulfide bonds such as plecanatide, uroguanylin, and dolcanatide.