Total synthesis of interleukin-2 via a tunable backbone modification strategy

Chemical synthesis of hydrophobic proteins presents a formidable task as they are often difficultly achieved via peptide synthesis, purification, and peptide ligation. Thus, peptide solubilizing strategies are needed to integrate with peptide ligation to achieve protein total synthesis. Herein, we report a tunable backbone modification strategy, taking advantage of the tunable stability of the Cys/Pen ligation intermediate, which allows for readily introducing a solubilizing tag for both peptide purification and ligation processes. The effectiveness of this strategy was demonstrated by the chemical synthesis of interleukin-2.