Solid-phase peptide synthesis (revision 3)

Solid-phase peptide synthesis (SPPS) assembles a peptide on an insoluble polymeric support. Because the growing chain is anchored, excess reagents and soluble by-products are removed simply by washing, which is what makes stepwise synthesis of long sequences practical.^[1]

The cycle is: remove the temporary N-terminal protecting group, wash, couple the next protected amino acid in excess, wash. Excess reagent drives each coupling towards completion, and the washing that removes it is the operation solution-phase synthesis cannot perform cheaply.^[2]

The resin is typically cross-linked polystyrene or a polyethylene glycol–polystyrene composite, functionalised with a linker that attaches the first residue and defines how the finished peptide is released.^[2]

The linker determines the C-terminal functionality. Wang and related linkers give a free acid on cleavage; Rink amide linkers give a C-terminal amide. Since several therapeutic peptides are C-terminally amidated, linker choice is a specification-level decision rather than a convenience.