Branched cyclic peptides

Scheme 12 Synthesis of branched cyclic peptides according to Bloomberg et al.

Polymyxins, fatty acid-containing, branched cyclic peptides produced by Bacillus polymyxa possessing antibiotic activity against Gram-negative bacteria. The structure of polymyxin Bi is shown as a member of this peptide group. The basic sequence of polymyxins consists of... 

Fig. 24. Cyclic peptide vaccine candidate bearing the minimally epitopic D1 branch of the Man9 G1cNAc2 antigen of HIV-1 gpl20 recognized by the protective human antibody 2G12.191...

Many variations of K2K dendrons have also evolved. A symmetrical version with a p-alanine spacer 39 at the a-amine of Lys provides a core unit that has symmetrical branching. To limit the flexibility of the branched lysyl template, ornithine, the lower homologue of Lys, as well as more constrained diamino acids 23-25 have been used. 39 62,64 Nonbranched polylysine dendrons 26 that are linear, and helical 71 and cyclic peptides 27 have also been developed to impart different forms of dendrimeric architecture (Scheme 5). 

Convergent ligation of cyclic peptide 86b (1.6 mmol) in twofold excess (8 equiv) of 93 (0.1 mmol) with a final concentration of 1-2 mM was performed in H20 at pH 8 with MeCN (50%) as a cosolvent to increase the solubility of 93. The ligation yielded >80% of the four-branch peptide dendrimer 94 (MALDI-MS mJz - calcd 8685.0 found 8685.7) together with <15% of the two- and three-branch dendrimers (MALDI-MS for three-branch dendrimer m/z calcd 6602 found 6604.0). After 45 min, the reaction was terminated and purified by RP-HPLC isolated yield 58%. 

Synthesis of Linear Branched, and Cyclic Peptide Chimera... 

An interesting example of a branched trimer containing (1 6)- and /3(1 2)-amide-linked sugars was supplied by Sicherl and Wittmann who devised mimetics of amino glycosides [37]. Pioneered by the group of Kessler [38] pyranoid sugar amino acid templates were described to represent turn mimetics and model peptides [39,40] including cyclic peptides [41,42]. As... 

In Fmoc chemistry, Lys and Om are conveniently blocked with the Boc protecting group [155]. For more temporary protection, the l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) protecting group is useful in the preparation of branched peptides, multiple antigenic peptides (MAPs), cyclic peptides, template-assembled synthetic proteins (TASPs), and templates for combinatorial chemistry [156-161]. Dde is quasi-orthogonal because the use of dilute hydrazine to cleave Dde partially removes the A -... 

The history of the major achievements concerning the isolation, structure elucidation, chemistry, and biological activity of the cyclic peptide principles of A. phalloides was comprehensively covered mainly by T. Wieland, a man of great merit particularly in this branch of natural products research. He dealt with the subject in several review articles 10,87,94,98-101) and more recently in an excellent book on the peptides of poisonous Amanita mushrooms 86). The number of references cited in the book exceeded 750, which gives a rough idea of the proportion of research carried out by chemists on this topic. The scope of the present chapter enables us only to summarize briefly the final results of these interesting studies. 

The synthesis of branched peptides using masked side-chain thioester derivatives of Asp and Glu which are compatible with Fmoc-SPPS is an important goal. Boll et al. synthesized cyclic and branched chain peptides using bis (2-sulfanylethyl)amido (SEA) side-chain derivatives of Asp and Glu via Fmoc SPPS [77]. The tail-to-side-chain cyclization via an in situ reduction of both acyclic and cyclic disulfides with tris(2-carboxyethyl)phosphine (TCEP) triggered the SEA intramolecular ligation. Glu derivatives cyclized more readily than the Asp analogues and without formation of side products (Scheme 9). 

Peptide Vaccines Peptide vaccines are chemically synthesized and normally consist of 8-24 amino acids. In comparison with protein molecules, peptide vaccines are relatively small. They are also known as peptidomimetic vaccines, as they mimic the epitopes. Complex structures of cyclic components, branched chains, or other configurations can be built into the peptide chain. In this way, they possess conformations similar to the epitopes and can be recognized by immune cells. An in silico vaccine design approach has been used to find potential epitopes. A critical aspect of peptide vaccines is to produce 3D structures similar to the native epitopes of the pathogen. 

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