Solid phase synthesis

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Author: R. Bruce Merrifield
Date: Apr. 18, 1986
From: Science(Vol. 232)
Publisher: American Association for the Advancement of Science
Document Type: Article
Length: 5,529 words

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Solid Phase Synthesis

THE PROTEINS, AS THE GREEK ROOT OF THEIR NAME implies, are of first rank in living systems, and their smaller relatives, the peptides, have now also been discovered to have important roles in biology. Among their members are many of the hormones, releasing factors, growth factors, ion carriers, antibiotics, toxins, and neuropeptides. My purpose today is to describe the chemical synthesis of peptides and proteins and to discuss the use of the synthetic approach to answer various biological questions.

The story begins with Emil Fischer (1) at the turn of this century when he synthesized the first peptide and coined the name. The general chemical requirements were to block the carboxyl group of one amino acid and the amino group of the second amino acid. Then, by activation of the free carboxyl group the peptide bond could be formed, and selective removal of the two protecting groups would lead to the free dipeptide. Fischer himself was never able to find a suitable reversible blocking group for the amine function, but his student Max bergmann, together with Leonidas Zervas, was successful (2). Their design of the carbobenzoxy group ushered in a new era. When I began working on the synthesis of peptides many years later, this same general scheme was universally in use and was very effective, having led, for example, to the first synthesis of a peptide hormone by du Vigneaud in 1953 (3). It soon became clear to me, however, that such syntheses were difficult and time consuming, and that a new approach was needed if large numbers of peptides were required or if larger and more complex peptides were to be made.

Synthesis on a Solid Matrix

One day I had an idea about how the goal of a more efficient synthesis might be achieved. The plan (4) was to assemble a peptide chain in a stepwise manner while it was attached at one end to a solid support. With the growing chain covalently anchored to an insoluble matrix at all stages of the synthesis, the peptide would also be completely insoluble and, furthermore, would be in a suitable physical form to permit rapid filtration and washing after completion of each of the synthetic reactions. The intermediate peptides in the synthesis would thus be purified by a very simple, rapid procedure rather than by the usual tedious crystallization methods. When a multistep process, such as the preparation of a long polypeptide or protein, is contemplated the saving in time, effort, and materials could be very large. The fact that all of the steps just described are heterogeneous reactions between a soluble reagent in the liquid phase and the growing peptide chain in the insoluble solid phase led to the introduction of the name "solid phase peptide synthesis."

The general scheme for solid phase synthesis is outlined in Fig. 1.

It begins with an insoluble particle (large circles), which is functionalized with a group, X. The first monomer unit (small circles) is blocked at one end...

Source Citation

Source Citation
Merrifield, R. Bruce. "Solid phase synthesis." Science, vol. 232, 18 Apr. 1986, pp. 341+. Accessed 30 Nov. 2022.
  

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