Peptides

Synthesis, Structures, and Applications

Bernd Gutte

• Publisher: Academic Press
• Year: 1995
• ISBN:
  9780080538594
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

In recent years, research has shown the importance of peptides in neuroscience, immunology, and cell biology. Active research programs worldwide are now engaged in developing peptide-based drugs and vaccines using modification of natural peptides and proteins, design of artificial peptides and peptide mimetics, and screening of peptide and phage libraries.

In this comprehensive book, the authors discuss peptide synthesis and application within the context of their increasing importance to the pharmaceutical industry. Peptides: Synthesis, Structures, and Applications explores the broad growth of information in modern peptide synthetic methods and the structure-activity relationships of synthetic polypeptides.

• The history of peptide chemistry
• Amide formation, deprotection, and disulfide formation in peptide synthesis
• Solid-phase peptide synthesis
• a-helix formation by peptides in water
• Stability and dynamics of peptide conformation
• An overview of structure-function studies of peptide hormones
• Neuropeptides: peptide and nonpeptide analogs
• Reversible inhibitors of serine proteinases
• Design of polypeptides
• Current capabilities and future possibilities of soluble chemical combinatorial libraries
• Epitope mapping with peptides
• Synthesis and applications of branched peptides in immunological methods and vaccines

1

The History of Peptide Chemistry

Theodor Wieland, Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany

I. Introduction

A. From Peptones to Peptides

B. The Structure of Proteins: Hofmeister–Fischer Theory

II. Early Peptide Syntheses

A. The Work of Theodor Curtius: The Azide Method

B. Emil Fischer’s Fundamental Efforts: Synthesis of an Octadecapeptide

C. The School of Emil Fischer: Abderhalden, Leuchs, and Bergmann

III. A New Era in Peptide Chemistry

A. Again Max Bergmann, and the Rockefeller Institute

B. Development of Additional Protecting Groups

C. New Methods for Forming the Peptide Bond

D. Solid-Phase Peptide Synthesis

IV. Classic Peptide Syntheses

A. Glutathione

B. Oxytocin and Vasopressin

C. Insulin

D. Depsipeptides and Cyclopeptides

V. Conclusion

References

I. Introduction

In the mid 1930s, when I began research in organic chemistry, the class of peptides was almost unknown. Studies of alkaloids and carbohydrates dominated the field of natural substances. There was little room for peptides, as traceable amounts of free peptides in natural material were practically absent, except glutathione and carnosine, and the few existing artificial peptides (as substrates for protein-cleaving enzymes) were interesting only to specialists. The significance and wide role of peptides in all life processes have only become apparent since the 1950s, owing to the continuous development of increasingly sensitive analytical, mainly chromatographic, methods. The still-increasing body of knowledge and compounds renders a brief account of the history of peptide chemistry, including the second half of the twentieth century difficult. It can be accomplished only by omitting important contributions. A brief history of peptide chemistry has been compiled by Wieland and Bodanszky (1991); for a review on the early synthesis of peptides, the collection by Fruton (1949) is instructive.

A. From Peptones to Peptides

By the mid-nineteenth century, egg white (albumen), milk casein, blood fibrin, gelatin, and cereal gluten were classified along with albumins as nitrogen-containing nutrients essential for life. In studies on the nature of these materials, it was also found that they were degraded by extracts from living organisms, such as pepsin from gastric juice and trypsin from pancreas. The products formed, called albumoses and peptones, were considered to represent the form in which the products of digestion were transported across the intestinal wall and used for the formation of proteins in the blood. Only in 1901 did Cohnheim show that the intestinal mucosa contained an enzyme, called erepsin, which cleaves peptones to amino acids. Amino acids had been isolated as components of proteins long before. Leucine was isolated from fermented wheat gluten and from casein by Proust in 1819 and tyrosine from an alkaline hydrolyzate of cow horn by J. Liebig in 1846. The first natural compound of this class, although recognized only 80 years later as an amino acid, was asparagine, which was crystallized from shoots of Asparagus by Vauquelin and Robiquet in 1806. For an historical review on discovery of amino acids, see Vickery (1972) and Vickery and Schmidt (1931); for a history of the resolution of the structure of proteins, see Fruton (1979).

This was the situation when Emil Fischer in 1899 embraced the field of protein chemistry that had been taboo for chemists because of the lack of adequate methods. Together with E. Fourneau he prepared the first free dipeptide, glycylglycine, by partial hydrolysis of the diketopiperazine, and at the fourteenth meeting of the German Natural Scientists and Physicians in Karlsbad, in 1902, he introduced the name “peptides.”

B. The Structure of Proteins: Hofmeister–Fischer Theory

At the same meeting, on the same day, in a plenary lecture entitled “Über den Bau der Eiweißstoffe” (“On the structure of proteins”) the physiologist and pharmacologist Franz Hofmeister (1850–1922) presented his views on the structure of proteins as long chains of α-amino acids linked to one another through amide bonds between carboxyl and amino groups (Hofmeister, 1902). Franz Hofmeister, then professor of physiological chemistry in Strassburg, among other topics had studied systematically the physical and chemical behavior of peptones and proteins (e.g., salting out, biuret reaction). The chemist Emil Fischer (1852–1919), who in 1896 had succeeded A. W. von Hofmann on the famous chemistry chair in Berlin and had entered the protein field only a few years previously, in his lecture “Über die Hydrolyse der Proteinstoffe” reported on the isolation of amino acids and additional compounds from protein hydrolysates and proposed the names dipeptide and tripeptide for dimeric and trimeric compounds. In his autoreferat (Fischer, 1902) he also wrote: “Finally the speaker discussed the coupling of the amino acids in proteins. The idea that acid–amide-like groups play the principal role most readily comes to mind [liegt am nächsten] as Hofmeister also assumed in his general lecture this morning.”

The structure of proteins as macromolecular polypeptides has been established and proved in several ways. The sequence of amino acids (primary structure) of innumerable peptides has been recognized by stepwise degradation or derived from corresponding DNA sequences, conformations of a great many of peptides have been determined (e.g., pleated sheet, α helix; Pauling et al., 1951) by optical or nuclear magnetic resonance (NMR) methods, and the molecular architecture of hundreds of proteins has been revealed by X-ray crystallography after the pioneering work of hemoglobin by Perutz et al. (1960) and on myoglobin by Kendrew et al. (1960). The success of such experiments depends on the quality of the protein crystals. Since the mid-1980s attempts have been made to grow better crystals in the low gravity environment of space. A review on this costly, only partially successful project has appeared (Stoddard et al., 1992).

In his Karlsbad lecture, Fischer also said that the idea of the amide-like connection had led him “more than 1½ years ago to initiate experiments to effect the synthetic linkage of amino acids.” That date, however, does not mark the origin of synthetic research with amino acids; this work began in 1882 and is connected with hippuric acid and the name of Theodor Curtius.

II. Early Peptide Syntheses

A. The Work of Theodor Curtius: The Azide Method

Theodor Curtius (1857–1928), the son of a dye manufacturer in Duisburg, took a doctorate in 1881 with Hermann Kolbe in Leipzig and on his suggestion reexamined the structure of hippuric acid, for which Dessaignes had proposed benzoylglycine as the formula. Curtius reacted glycine–...