An Iodine-Free and Directed-Disulfide-Bond-Forming Route to Insulin Analogues

An iodine-free synthetic route to insulin analogues has been established via a directed disulfide bond formation strategy. This method is completely compatible with oxidation-sensitive residues. The key step is constructing the third disulfide bond via a novel procedure involving phenylacetylaminomethyl group (Phacm), immobilized Penicillin G Acylase, and Ellman's reagent. We expect that this method could be broadly utilized for synthesizing insulin-like and other cysteine-rich peptides, in particular, where oxidation-sensitive residues are present in the sequence.