The New Salicylaldehyde <i>S</i>,<i>S</i>-Propanedithioacetal Ester Enables N-to-C Sequential Native Chemical Ligation and Ser/Thr Ligation for Chemical Protein Synthesis
Dong‐Liang Huang, Ying Li, Jun Liang, Lu Yu, Min Xue, Xiuxiu Cao, Bin Xiao, Changlin Tian, Lei Liu, Ji‐Shen Zheng
Abstract
The combination of distinct peptide ligation techniques to facilitate chemical protein synthesis represents one of the long-standing goals in the field. A new combination ligation method of N-to-C sequential native chemical ligation and Ser/Thr ligation (NCL-STL) is described for the first time. This method relies on the peptide salicylaldehyde S,S-propanedithioacetal (SALPDT)-ester prepared by a new 1,3-propanedithiol-mediated reaction. The peptide SALPDT-ester, which is compatible with NCL, can be fully activated by N-chlorosuccinimide (NCS)/AgNO3 in aqueous solution to afford peptide SAL-ester for use in the subsequent STL. The practicality of the combined NCL-STL method is illustrated by the synthesis of S-palmitoylated matrix-2 (S-palm M2) ion channel from Influenza A virus and S-palmitoylated interferon-induced transmembrane protein 3 (S-palm IFITM3). This approach expands the multiple-segments peptide ligation toolkit for producing important and complex custom-made protein samples by chemical protein synthesis.