Macrocyclic peptide structures

Two important examples of cyclic peptides will be highlighted in which amino acid sequences of larger proteins have been successfully used as part of macrocyclic peptide structures to mimic in an almost pars pro toto approach important properties of the parent protein. 

Structural determination of macrocyclic peptides cyclosporins by mass spectrometry 97CLY2. 

Substitution of the terminal amine with ligating groups, such as catecholate, hydrox-amate or diketonate, lead to the formation of A-cis chiral complexes. In these structures the chiral information content is located in the amino acid bridges, instead of the macrocyclic peptide ring structure used in ferrichrome. It should be emphasized... 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

Phan, J., Shi, Z-D., Burke, T.R., Jr., and Waugh, D.S. (2005) Crsytal structures of a high-affinity macrocyclic peptide mimetic complex with the Grb2 SH2 domain. J.Mol. Biol. 353,104-115. 

Yamashita T, Kojima Y, Hirotsu K, Ohsuka A. Macrocyclic peptides. Synthesis and structure of a novel dipeptide, (2S, 3 S)-2-(2 -oxo-3 -methylpiperazin- l -oxyl)-propanoic acid, and its use as the unit of cychc peptides. Int. J. Pept. Protein Res. 1989 33 110-114. 

DFPQIMRIKPHQGQHIGE) but not the linear control (PQIMRIKPEIQGQHIGE) competed for receptor binding. The addition of 2, 2, 2-trifluoroethanol to an aqueous solution of cyclo-VEGI stabilized helical conformations in the 1-8 domain. This was unexpected because P-sheet structures and random coil conformations are those observed in macrocyclic peptides. In cyclo-VEGI, Pro-2 induces helix formation and Pro-9 breaks the 1-8 helical domain. 

Macrocyclization by the Heck reaction has been shown to be a useful method in the preparation of new cyclic peptide structures. 

The final chapter, by Itokawa, Takeya, Hitotsuyanagi, and Morita, reviews the various macrocyclic peptide alkaloids isolated from plants. In addition to a general overview of the many new peptide and amide alkaloids that have been isolated recently from a diverse range of plant families, this review places particular emphasis on the structure-activity relationships, the conformational analysis, and the antitumor activity of the RA series of cyclic oligopeptides from Rubia spp. 

Thiopeptide antibiotics, thiazolyl peptides, naturally occurring sulfur-containing, highly modified, macrocyclic peptides. They share a number of structural motifs, including several heterocycles such as thiazoles, a dehydropiperidine, a pyridine, oxazoles, and indoles. Nearly aU of the thiopeptide antibiotics act as inhibitors of protein synthesis in bacteria. They are secondary metabolites produced by actino-mycetes, largely by the genus Streptomyces. A representative member of this family is thiostrepton [M. C. Bagleyetal., Chem. Rev. 2005, 105, 685]. 

In 1955, H. Brockmann and Schmidt-Kastner [15] isolated an antibiotic substance from extracts of Streptomyces fulvissimus. They named it valinomycin after valine having been found as the only amino acid in the acid-hydrolyzate. Since no amino group nor carboxyl group could be detected in the substance which was almost insoluble in water, a cyclic structure had to be assumed. Valinomycin has a macrocyclic molecular structure consisting of three identical tetradepsipeptide fragments with alternating peptide and ester bonds between D-a-hydroxyisovaleric acid, D-valine, L-lactic add, L-valyl residues (Fig. 10). 

Figure 8 (a) /3-Barrel nanotube structure derived from a macrocyclic peptide that contains an a-helix and /S-sheet segments. 

The elucidation of the structure of telomycin, a macrocyclic peptide lactone, discloses the presence of three novel amino acids, erythro-3-hydroxyleucine, cis- and trans-3-hydroxy-proline the unusual chromophore in this antibiotic (X max 339 mp e = 22,000) is another example of a dehydroamino acid (dehydrotryptophan) unit (XIl). 

C5a is a 74-amino acid glycoprotein. The structure in solution was found to be a 4-helix-bundle containing the receptor recognition domain with the C-terminus effector domain being responsible for receptor activation." " This latter domain was first described to be unstructured" and more recently to adopt an a-helical conformation spanning residues 69-74. Inspired by these findings, macrocyclic peptides such as the derivative PMX-53 (22, Figure 8.9, Table 8.2) were developed. ... 

A number of innovative methods for macrocycle synthesis have attempted to harness the power and selectivity of biological methods in conjunction with one or more chemical transformations. These hybrid processes have by necessity focused on peptidic structures, often relatively large in ring size, but also have proven very capable of the rapid synthesis of extremely high numbers of macrocyclic compounds. Several recent reviews have detailed these strategies, some of the most useful of which will be outlined here. - ... 

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