Synthesis of homogenous disulfide cross-linked polypeptides by iterative reducible ligation

A new method of directed solution phase synthesis of polypeptides linked through iterative formation of disulfide bonds is reported. Four dodecapeptides were successfully ligated into a single 48 amino acid polypeptide using an N-terminal Fmoc-thiazolidine and a novel acidic silver trifluoromethanesulfonate thiazolidine hydrolysis to achieve efficient ligation in the presence of internal disulfide bonds. The approach allows the synthesis of homogeneous disulfide cross-linked polypeptides that have application in gene delivery by undergoing a reductively triggered release of DNA.