New chemistries for chemoselective peptide ligations and the total synthesis of proteins

• Native chemical ligation is a powerful approach to the synthesis of many proteins.
• KAHA ligation with 5-oxaproline offers easy access to depsipeptides.
• Serine/threonine ligation is a versatile and efficient method.
• Azide–alkyne ligation is a new peptidomimetic ligation prototype and leads to bioactive backbone-modified proteins.
• KAT ligation affords synthetic access to a great number of protein conjugates.

The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical ligation — an N-terminal cysteine and C-terminal thioesters — have encouraged a search for alternative amide-forming ligation reactions. Among successful alternatives to native chemical ligation, are the α-ketoacid–hydroxylamine ligation with 5-oxaproline and, serine/threonine ligation, and potassium acyltrifluoroborate (KAT) ligation. In addition, the KAT ligation, along with the non-amide forming alkyne–azide ligation, is very useful for synthetic conjugations. All of these recent ligation methods were applied to synthesize different proteins, and have allowed chemists to incorporate unnatural amino acids, or to modify the peptide backbone.