Cyclic peptide libraries

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

Cyclic Peptide Libraries with Sequential and Chemical Diversity... 

An additional problem arises with the difficult analytical characterization of the cyclic peptide libraries. This is preferably performed by mass spectrometry, although there are limitations with the ionization method. In fact, FAB-MS leads to overexpression of hydro-phobic components by ion suppression, whereas in MALDI-MS preferentially hydrophilic... 

In addition to sequential and chemical diversity, cyclic peptide libraries offer the possibility of conformational diversity where all components of the library differ from each other in their conformation, despite the identical connectivity. In this context two complementary approaches have been proposed, i.e. spatial screening based on head-to-tail cyclic peptides and cycloscan where the rest of the modes of cyclization are exploited. 

On-Resin Synthesis of a Cyclic Peptide Library Using Lys and Glu Side-Chains... 

Figure 4.19 Structure of phage display S-S cyclic peptide libraries L28-L30.

Fig. 3. Several linkers used for cyclization. For backbone linkers 1 and 2 small libraries of cyclic peptides have been synthesized (26-28). Activated linkers 4 to 6 have also been used in cyclic peptide libraries (29-32).

Spatola, A. F., Darlak, K., and Romanovskis, P. (1996) An approach to cyclic peptide libraries reducing epimerization in medium sized rings during solid-phase synthesis. Tetrahedron Lett, yi, 591-594. 

Darwen, P. J., Bourne, G. T., Nielson, J., Tran, T. T., and Smythe, M. L. (2003) A gradient descent algorithm for minimizing the number of steps required for synthesis of cyclic-peptide libraries. Personal communication. 

Joo SH, Xiao Q, Ling Y, Gopishetty B, Pei D. High-throughput sequence determination of cyclic peptide library members by partial edman degradation/mass spectrometry. J. Am. Chem. Soc. 

Peptide Libraries with Specific Structural Eleuieuts 4.3.7.2.1 Cyclic Peptide Libraries... 

The two most common reactions for the generation of cyclic peptides are (i) disulfide formation between cysteine or penicillamine residues through oxidation, and (ii) lactam formation between the amino and carboxy terminal ends (head-to-taU cyclization), the annino terminus and the side chain of an aspartic or glutanoic add residue, or between the side chains of a lysine (or another diamino acid) and aspartic or glutanoic acid residues. A special mode of the second type is backbone cyclization between an amino group (N-terminal or side chain) and a carboxyalkylated backbone nitrogen. Both reactions have been used to generate cyclic peptide libraries. 

T.M. Kinsella, C.T. Ohashi, A.G. Harder, G.C. Yam, W. Li, B. Peelle, E.S. Pali, M.K. Bennett, S.M. Molineaux, D.A. Anderson, E.S. Masuda, D.G. Payan, Retrovirally delivered random cyclic Peptide libraries yield inhibitors of interleukin-4 signaling in human B cells, J. Biol. Chem. 2002, 277, 37512-37518. 

As an important feature, a linker group can be attached to the tricyclic skeleton of 12 which results in the possibility to attach the template onto a solid support and synthesise template-bridged cyclic peptide libraries using the split synthesis. 

Scheme 20 Synthesis of CPE peptide in the translational system and formation of the cyclic peptide library...

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