Native Chemical Ligation of Peptides and Proteins

For over 20 years, native chemical ligation (NCL) has played a pivotal role in enabling total synthesis and semisynthesis of increasingly complex peptide and protein targets. Classical NCL proceeds by chemoselective reaction of two unprotected polypeptide chains in near‐neutral‐pH, aqueous solution and is made possible by the presence of a thioester moiety on the C‐terminus of the N‐terminal peptide fragment and a natural cysteine residue on the N‐terminus of the C‐terminal peptide fragment. The reaction yields an amide bond adjacent to cysteine at the ligation site, furnishing a native protein backbone in a traceless manner. This unit highlights a number of recent and powerful advances in the methodology and outlines their particular uses, facilitating application in the synthesis of challenging protein targets. © 2019 by John Wiley & Sons, Inc.