Bis(2-sulfanylethyl)amido Peptides Enable Native Chemical Ligation at Proline and Minimize Deletion Side-Product Formation

Native chemical ligation of C-terminal peptidyl prolyl alkylthioesters with N-terminal cysteinyl peptides usually exhibits poor kinetic rates compared to other C-terminal amino acid residues. It is shown here that the reaction is accompanied by the formation of a deletion side product which is minimized by using a bis(2-sulfanylethyl)amido (SEA) thioester surrogate at a mildly acidic pH.