Peptides cyclopeptides

Key Words Chimeric peptide cyclopeptide solid phase peptide synthesis thio-ether bond disulfide bridge herpes simplex virus glycoprotein D peptide epitope oligotuftsin carrier molecule. 

Kleinkauf H, von Dohren H. The nonribosomal peptide biosynthetic system—on the origins of structural diversity of peptides, cyclopeptides and related compounds. Antonie van Leeuwenhoek 1994 67 229-242. 

The cyclopeptide described above was tailored to form stable potassium complexes. It is one of the very few examples of complex peptide syntheses which do not lead to a natural compound. 

Fig. 3-3. Comparison of the values of enantiomeric resolution of different DNP-D,L-amino acids at different deconvolution stages of a cyclic hexapeptide sublibrary. Resolution values in a cyclo(Arg-Lys-X-X-X-P-Ala) sublibrary, in the first line, are compared to those obtained in sublibraries with a progressively increasing number of defined positions. All the sublibraries were 30 mM in the running buffer while the completely defined cyclo(Arg-Lys-Tyr-P-Tyr-P-Ala) peptide is used at 10 mM concentration. Conditions cyclopeptide sublibrary in 20 mM sodium phosphate buffer, pH 7.0 capillary, 50 pm i.d., 65 cm total length, 57 cm to the window V = -20 kV, I = 40 electrokinetic injection, -10 kV, 3 s detection at 340 nm. (Reprinted with permission from ref. [75]. Copyright 1998, American Chemical Society.)...

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

Wakselman, M. Mazaleyrat, J.-P. Lin, R. C. Xie, J. Vigier, B. Vilain, A. C. Fesquet, S. Boggetto, N. Reboud-Ravaux, M. Design, synthesis and study of a selective cyclopeptidic mechanism-based inhibitor of human thrombin. In Peptides Chemistry, Structure... 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

Numerous peptides have been prepared starting from trifluoromethylalanine. 31, 120 Cyclopeptides containing a-trifluoromethyl amino acids have also be prepared. Some peptidic coupling performed with other a-trifluoromethyl amino acids involve protease catalysis (subtilisin, a-chymotrypsin, carboxypeptidase Y, trypsin, etc.). ... 

If an asymmetric hydrogenation of C=C bonds is desired in the presence of achiral catalysts, chiral information is required to be present in the substrate. Peptides and cyclopeptides containing dehydroaminos acid units are very good substrates achieving quite high stereoselectivities upon asymmetric hydogenation on 10% Pd-C or other achiral catalysts 49 841. 

Peptides with more than seven amino acids can usually be cyclized without problems, but smaller cyclopeptides can be difficult to prepare. Few examples of the preparation of cyclotetrapeptides have been reported [61,62]. The preparation of cyclo-pentapeptides proceeds satisfactorily in solution with HOAt-derived coupling reagents [63,64],... 

CNMR investigations of several cyclic and acyclic peptide antibiotics and toxins have been reported in the literature, e.g., gramicidin S-A (cyclo(Phe-Pro-Val-Orn-Leu)2) [176, 801, 872 875], viomycin (cyclopeptide constituted of L-serine, at, I-L-di-aminopropionic acid, /J-L-lysine and viomycidine) [876], bacitracin A (Ile-Cys-Leu-D-Glu-Ile-Lys-n-Orn-Ile) [815], alamethicin (Ac-Aib-Pro-Val-Aib-Val-Aib-Aib-Ala-Aib-... 

Cyclopeptides.1 Cyclization of polypeptides under conditions of high dilution usually proceeds in low yield. A new method involves cyclization of co-peptide-pentafluorophenyl esters in dioxane in the presence of 4-pyrrolidinopyridine and an alcohol (ethanol or f-butyl alcohol). p-Nitrophenyl esters can also be employed, but separation of p-nitrophenol from product is more difficult than that of pen-tafluorophenol. 

The term peptide alkaloid was first proposed by Goutarel and co-workers. However, since these alkaloids, with one known exception, are cyclic ones the term cyclopeptide alkaloids seems to be more appropriate the lone exception (lasiodine-A) could in fact arise by secondary opening of the cyclic system. In this review only those alkaloids are treated which incorporate a hydroxystyrylamino group... 

The zizyphine-A type are 13-membered cyclopeptides composed of / -(2-methoxy-5-hydroxyphenyl)vinylamine, 3-hydroxyproline, and another amino acid. The first known representative was described as zizyphine in 1965 and given an open chain structure (13). It was subsequently renamed zizyphine-A in view of a further examination of Zizyphus oenoplia which disclosed other peptide alkaloids (14). 

Bishay and co-workers (5) postulated a possible correlation between cyclopeptide and tetrahydroisoquinoline alkaloids when they isolated R-( — )-armepavine as well as franguline-type bases from Euonymus europaeus. Pailer and Haslinger (45) isolated, in addition to the known peptide alkaloids, the same armepavine during a renewed examination of Rhamnus frangula. 

Enniatins belong to the class of A-mcthylatcd cyclopeptides which are produced by various strains of the genus Fusarium [12], As shown in Figure 1, enniatins consist of alternating residues of D-2-hydroxyisovaleric acid (D-Hiv) and a branched chain A-methyl-L-amino acid, linked by peptide and ester bonds. In the case of beauvericin the branched chain L-amino acid is substituted by L-phenylalanine (Fig. 1). 

Systematic investigations revealed that anion binding is mainly prevented by the steric effects of the aromatic substituents. A cyclopeptide with methyl groups on the aromatic rings, for example, also binds no anions. The high cation affinity of 4a and 4b has to be attributed to the stabilizing effects of the aromatic substituents on peptide conformation, however, because the methyl-substituted peptide, in which the amide groups are not fixed in a certain orientation, has a cation affinity that is even lower than that of 3 [18]. 

This crystal structure shows that the iodide forms hydrogen bonds to all six NH of the two peptide moieties in the complex. It also demonstrates how effectively the anion is embedded between the cyclopeptides. Complex formation thus shields the guest from surrounding solvent molecules, an effect that strengthens receptor-substrate interactions this might be one reason for the anion affinity of 5 in aqueous solution. 

To improve the aqueous solubility of 5 we also synthesized a cyclopeptide 6 containing hydroxyproline subunits [24]. Although this compound is very water-soluble, and in solution adopts a similar conformation to 5, it only forms 1 1 complexes with anions. A reason for the inability of 7 to form 2 1 complexes could be that the hydroxyproline subunits in 6 are better solvated than prolines in aqueous solution, and the desolvation required for aggregation of two cyclopeptide molecules thus occurs less readily. Steric hindrance of hydroxyl groups from different cydopeptide moieties in the a dimeric complex of 6 could, moreover, also make aggregation difficult. Although peptide 6 cannot form sandwich-type complexes, it proved to be valuable for a quantitative determination of the anion affinity of 5, the results of which are summarized in Table 2.2.3 [24],... 

In summary, our approach of using cyclopeptides with natural amino acids and 3-aminobenzoic acid subunits for the development of macrocydic receptors has afforded remarkably efficient hosts. The cation affinity of 4b, for example, exceeds that of many calixarene derivatives. Even more interesting is the high anion affinity of 5 in aqueous solution. By introdudng additional functional groups such as car-boxylates to the periphery of the cavity, we recently also obtained cydopeptides that interact with neutral substrates, for example, carbohydrates [25]. Our peptides therefore represent a versatile dass of artificial receptor that should prove useful in supramolecular and bioorganic chemistry. 

Two linkers particularly suitable for peptide amides and cyclopeptides are the peptide amide linker (PAL) and the backbone amide linker (BAL) [29] (Scheme 6.1.3). With these electronic and steric factors enable acylation of secondary ben-zylamines and relatively mild cleavage. 

Peptides can be used to direct the nanoscale assembly of amphiphilic synthetic polymers. A common feature is that the self-assembly of the peptides proceeds as it would do in the absence of the polymer conjugates, with the peptide suprastructure forming a core, surrounded by the polymer random coil. The polymer shell acts to limit aggregation of the peptides beyond a certain size limit. A particularly striking example of this is the self-assembly of cyclopeptide-polymer composites, which form hollow... 

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