Solid-phase peptide synthesis is the method introduced by Bruce Merrifield in 1963, for which he received the 1984 Nobel Prize in Chemistry. The chain is anchored by its C-terminus to an insoluble polymer bead and extended toward the N-terminus. Each residue requires one round of deprotection, coupling with an activated and side-chain-protected amino acid, and washing — because the growing chain is immobilised, excess reagents are simply rinsed away rather than separated chromatographically.
Why SPPS matters in peptide research
Coupling efficiency sets the ceiling on achievable purity, and the arithmetic is unforgiving. At 99% per step, a 30-residue peptide yields about 74% full-length product; at 98%, only 55%. Everything else is deletion and truncation sequences that must be removed by preparative HPLC, which is why longer peptides cost disproportionately more per milligram and why chemical synthesis gives way to recombinant expression above roughly 50 residues.
Modern practice uses Fmoc chemistry with piperidine deprotection and cleavage in trifluoroacetic acid, which is how peptides end up as a TFA salt unless exchanged. Difficult sequences with aggregating stretches drive efficiency down. See synthetic peptides and HPLC purity explained.
Related terms
protecting group · purity · peptide bond