Solid phase peptide synthesis

In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds, also known as peptide bonds. The biological process of producing long peptides (proteins) is known as protein biosynthesis.

Peptides are synthesized by coupling the carboxyl group of one amino acid to the amino group of another amino acid molecule. Due to the possibility of unintended reactions, protecting groups are usually necessary. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide, and proceeds toward the amino-terminus. This is the opposite direction of protein biosynthesis.

Liquid-phase peptide synthesis is a classical approach to peptide synthesis. It has been replaced in most labs by solid-phase synthesis (see below). However, it retains usefulness in large-scale production of peptides for industrial purposes.

Solid-phase peptide synthesis (SPPS), pioneered by Robert Bruce Merrifield, caused a paradigm shift within the peptide synthesis community, and it is now the standard method for synthesizing peptides and proteins in the lab. SPPS allows for the synthesis of natural peptides which are difficult to express in bacteria, the incorporation of unnatural amino acids, peptide/protein backbone modification, and the synthesis of D-proteins, which consist of D-amino acids.

Small porous beads are treated with functional units ('linkers') on which peptide chains can be built. The peptide will remain covalently attached to the bead until cleaved from it by a reagent such as anhydrous hydrogen fluoride or trifluoroacetic acid. The peptide is thus 'immobilized' on the solid-phase and can be retained during a filtration process while liquid-phase reagents and by-products of synthesis are flushed away.

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