Orthogonal ligation strategies for peptide and protein

This review focuses on the concept, criteria, and methods of an orthogonal amide ligating strategy suitable for syntheses of peptides, peptide mimetic s, and proteins. Utilizing unprotected peptides or proteins derived from ch emical or biosynthetic sources, this ligation strategy has been shown to be general and exceptionally mild. Its orthogonality in ligating two unprotec ted segments with free N-terminal (NT)-amines at a specific NT-amine is ach ieved through a chemoselective capture step and then an intramolecular acyl transfer reaction. Both coupling reagents for enthalpic activation and pro tection schemes therefore become unnecessary. More than a dozen orthogonal ligation methods based on either imine or thioester captures have been deve loped to afford native and unusual amino acids at ligation sites of linear branched, or cyclic peptides. Because unprotected peptides and proteins of different sizes and forms can be obtained from either chemical or recombina nt sources, orthogonal ligation removes the size limitation imposed on the chemical synthesis of a protein with a native or non-native structure. Furt hermore, by using building blocks from biosynthetic sources, orthogonal lig ation provides a unifying operational concept for both total and semisynthe sis of peptides and proteins. (C) 2000 John Wiley & Sons, Inc.