Synthesizing Proteins in Solid Beads

Any chemist knows that the more steps there are in a chemical synthesis, the lower the final yield. For example, if each step in a 10-step synthesis furnishes a 90 percent yield of product, the yield of the final product will be only about 35 percent. That is why it is not possible to extend Du Vigneaud s masterful syntheses (see chapter 6) of the hormones oxytocin and vasopressin (9 amino acid residues each) to proteins, even small ones such as ribonuclease A (124 amino acid residues). In order to pursue this daunting challenge Robert Bruce Merrifield (1921-2006), at Rockefeller University, devised a new concept solid-phase synthesis. The idea is disarmingly simple covalently attach an amino acid to a macroscopic particle that can be exposed to the reaction, washed, and then separated by simple filtration. Each reaction step requires no chromatography and no crystallization, just washing and filtering. At the end, completed peptide chains are chemically released from the particles. 

The diagram on page 244 depicts the Merrifield synthesis. The resin ( R ) is composed of beads of styrene, copolymerized with 1 

The steps in the Merrifield solid-phase peptide and protein synthesis attachment of an amino acid to a polymer head followed hy cycles of attachment of other amino acids allows extremely high yield syntheses at each step and acceptable yields for syntheses that exceed 100 amino acid condensations. 

N - protected amino acid attached to solid-phase beads-separate and wash beads 

N protection removed from amino acid attached to resin 

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