Klaus Lübke

d-Aminosäurehaltige Analoga des Eledoisins

The synthesis of several C-terminal eledoisin heptapeptide analogues, containing 1–5d-amino acids, is described and the biological activities are discussed.

Über den Einfluss der Kettenlänge auf die biologische Aktivität eledoisinanaloger Verbindungen

The syntheses of Eledoisin analogues by shortening the peptide chain at the N-terminal moiety of the molecule are described. The influence of the chain length on the hypotensive activity is discussed.

Isolation and structure of N α -formyl melittin

Bienengift wurde durch Gelfiltration in seine Komponenten aufgetrennt. Aus der Melittinfraktion wurde neben Melittin eine elektrophoretisch langsamer wandernde Komponente isoliert, die als N α -Formyl-Melittin identifiziert wurde. Diese Struktur wurde auch durch Synthese bestätigt.

FORMATION OF THE PEPTIDE BOND

This chapter discusses the formation of the peptide bond. The activation of a carboxyl group by anhydride formation is more pronounced when the second acid displays strong electron-attracting properties. This is clearly demonstrated by the mixed anhydrides with inorganic acids. Organic acids, especially carboxylic acids as anhydride components, may disproportionate to form symmetrical anhydrides. The active intermediate of the activation of the amino group by phosphorus pentoxide is supposedly a phosphoric acid monoethyl ester monamide. It apparently results from the reaction of phosphorus pentoxide with the diethyl phosphite used as solvent. The amino group is capable of amide formation by way of its free electron pair without additional activation. Therefore, the assumption was made that peptide syntheses by activation of the amino group proceed via an intermediate activated at the carboxyl group. This intermediate would result from the addition of the activated amino component to the carboxyl group.

AMINO-PROTECTING GROUPS

This chapter discusses amino-protecting groups. The simple acyl groups are not suitable as amino-protecting groups. They form a new amide bond that would be difficult to cleave selectively in the presence of other peptide bonds. A rearrangement common to all acylamino acids—the azlactone formation—limits severely the application of these residues as protecting groups as the optical activity may be extinguished because of the formation of tautomers. Monoalkylation normally does not provide complete protection of the amino function. It can still be acylated, although with greater difficulty. The amino group is fully blocked in dialkylated derivatives. Protonated amino groups are important for the synthesis of peptides in only a few special cases. This is in contrast to the protection of the carboxyl group by salt formation. Protonation becomes essential for the prevention of side reactions during the synthesis of amino acid and peptide derivatives.

HETERODETIC CYCLIC PEPTIDES

Extracts of the posterior lobe of the pituitary gland display anti-diuretic properties, increase blood pressure, enhance lactation, and contract the uterus. In mammals, these effects are because of the presence of the peptide hormones oxytocin and vasopressin. The hormones of the posterior lobe are produced in certain neurons of the hypothalamus. They are most likely transferred to the posterior lobe to be stored, via the axoplasmic circulation. The two hormones are secreted simultaneously although in different quantities. Vasotocin, structurally and pharmacologically related to oxytocin and vasopressin, was found in the pituitary of lower vertebrates. Isotocin has been isolated from the pituitary of various species of fish, and mesotocin from frog pituitaries. The elucidation of the structures of oxytocin and vasopressin and their synthesis made possible studies on the relationship between structure and pharmacological action. These investigations have contributed to the understanding of the physiology of the neurohypophysis.

The Influence of Substitution or Omission of an Amino Group on the Hypotensive Activity of the C-Terminal Sequences of Eledoisin

Our knowledge about the relation between structure and activity in the peptide field originates almost completely from changes in the amino acid sequence or chain length of the native molecule. Only little is known about the influence of the substitution of functional groups by nonpeptidic residues. In some cases, however, the importance of unsubstituted functional groups is established, as well as the possibility of substitution or omission of some functional groups without reducing the activity to a large extent.

HOMODETIC CYCLIC PEPTIDES

The homodetic cyclic biologically active peptides might be subdivided into homomeric peptides and heteromeric peptides. The two types have the homodetic cyclic peptide structure in common. The heteromeric peptides contain a hetero component, linked to the cyclic structure via a diaminocarboxylic acid. The hetero component is a fatty acid. To the class of homodetic cyclic homomeric peptide antibiotics belong gramicidin S, the tyrocidines, evolidin, fungisporin, and mycobacillin. The bacitracins are homomeric peptides, containing a thiazoline ring in the peptide side chain. This chapter discusses the origin and biological activities of gramicidins A, B, and C that have been shown to be linear peptides. A metabolic product of a fungus without antibiotic activity was found in malformin. Heterodetic cyclic heteromeric peptides include the polymyxins, circulins, and colistins. The toxins of the death cap are homodetic cyclic peptides, bridged via the sulfhydryl group of cysteine.

I – LINEAR PEPTIDES

Publisher Summary The term “tissue hormones” covers biologically active polypeptides that are not secreted by a special gland, but are released from inactive precursors in blood plasma or diffuse storage depots. The name “plasma kinin” had been suggested for polypeptides of bradykinin-like pharmacological properties. The term “kinin” is to be applied to all tissue hormones of peptide nature that act upon smooth muscle and display vasoactive properties. This definition excludes the hormones of the neurohypophysis; it covers the angiotensins and substance P. It was found that renin is a high molecular, non-dialyzable, thermolabile protein. The low molecular weight polypeptide angiotensin, which is the actual substance with pressor activity, is released from an inactive precursor in blood plasma by the proteolytic action of rennin. When the serum protein fraction from which angiotensin and bradykinin are liberated is incubated with pepsin, polypeptides possessing pressor, oxytocic, and diuretic activities are released. These substances have been isolated in small quantities and only a few have been described as chromatographically and electrophoretically pure compounds.

THE PLASTEIN REACTION

This chapter discusses plastein reactions. Certain proteolytic enzymes initiate the formation of high-molecular, protein-like substances when allowed to act upon concentrated solutions of enzymatically cleaved proteins. The investigations of this enzymatic peptide synthesis were, until recently, restricted to peptide mixtures obtained by proteolytic digestion of proteins. Differences in the amino acid composition of plastein from that of the applied hydrolyzate have led to the conclusion that not all peptides present in the reaction mixture participate in the plastein formation. The plastein formation is accompanied by proteolysis if the peptides applied are too long. The molecular weights of plasteins obtained with chymotrypsin vary from 250,000 to 500,000. Some of these molecular weights are higher than those of the native proteins that were originally hydrolyzed. After the successful synthesis of plastein-active peptides, more reliable statements on the mechanism of the plastein reaction became possible. Thus, at least the plastein reaction catalyzed by pepsin resembles dehydration, and this seems to apply with a high degree of certainty to the reaction catalyzed by chymotrypsin. The isolated plasteins contain the same amino acids in the same ratios as the starting peptides.