Peptide synthesis (revision 4)

Peptide synthesis is the chemical assembly of a peptide from protected amino acid building blocks. It proceeds from the C-terminus towards the N-terminus, in the opposite direction to biological translation, because that ordering avoids racemisation of the activated residue.^[1]

Chemical synthesis is the only practical route for peptides containing non-proteinogenic residues, and almost every engineered therapeutic peptide contains at least one — the α-aminoisobutyric acid of semaglutide and tirzepatide cannot be introduced by a ribosome.^[2]

Each residue is added by a two-step cycle. The N-terminal protecting group of the growing chain is removed, then the next amino acid — protected at its own N-terminus and on any reactive side chain — is activated and coupled.^[1]

Protecting groups are what make selectivity possible. The temporary N-terminal group is removed once per cycle; side-chain groups are orthogonal to it and survive until final cleavage. The choice of scheme — Fmoc with acid-labile side chains, or Boc with more forcing conditions — defines the whole chemistry that follows. See Fmoc chemistry.