Chemical Synthesis of Interleukin‐2 and Disulfide Stabilizing Analogues

Chemical protein synthesis allows the construction of well‐defined structural variations and facilitates the development of deeper understanding of protein structure–function relationships and new protein engineering strategies. Herein, we report the chemical synthesis of interleukin‐2 (IL‐2) variants on a multimilligram scale and the formation of non‐natural disulfide mimetics that improve stability against reduction. The synthesis was accomplished by convergent KAHA ligations; the acidic conditions of KAHA ligation proved to be valuable for the solubilization of the hydrophobic segments of IL‐2. The bioactivity of the synthetic IL‐2 and its analogues were shown to be equipotent to recombinant IL‐2 and exhibit improved stability against reducing agents.