Sequential Peptide Ligation by Combining the Cys–Pro Ester (CPE) and Thioester Methods and Its Application to the Synthesis of Histone H3 Containing a Trimethyl Lysine Residue

Abstract A peptide thioester is a key building block for protein synthesis by a ligation method, such as the thioester method and native chemical ligation. Combining these ligation methods offers flexibility in the choice of the condensation sites in a sequential ligation strategy. We describe herein a novel strategy, in which native chemical ligation followed by the thioester method are utilized, based on the use of a peptide containing a Cys–Pro ester (CPE) autoactivating unit at the C-terminus as a peptide thioester precursor. This sequential ligation strategy was applied to the synthesis of histone H3, which consists of 135 amino acid residues and contains a trimethyl Lys9 residue.