Cyclic peptides, design

Figure 20. Schematic diagram of the donor-acceptor site interaction between two molecules of deoxyhemoglobin S with two cyclic peptides designed to mimic the donor site (206).

The same method can be used for the construction of Asn- or Gin-containing head-to-tail cyclic peptides, using a benzhydrylamine instead of a benzyl alcohol linker, as shown by Tromelin et al. [19]. The synthesis of an 18-mer head-to-tail cyclic peptide designed to mimic a loop involved in the curaremimetic action of a snake toxin protein, cycto(Asn-Tyr-Lys-Lys-Val-Trp-Arg-Asp-His-Arg-Gly-Thr-Ile-Ile-Glu-Arg-Gly-Pro), was prepared. 

Three cyclic peptides designed to exemplify different features of peptide conformation have been studied by solid-state NMR ( ), solution NMR (Ifl, j,8) and X-ray diffraction (16). The NMR results described here in brief fonn show a variety of interesting phenomena for these peptides, Cvclo(D-Phe-Pro-Glv-D-Ala-Pro) is a rigid cyclic pentapeptlde which contains in solution... 

Recently, Tam et al. extended their orthogonal ligation concept, using the thermodynamically driven formation of a thiazolidine ring for the synthesis of dendritic compounds that carry cyclic peptides at the surface, which were designated multiple cyclic antigen peptides (McAPs) [18,19]. 

The widespread occurrence of cyclic peptides and depsipeptides in natura makes the research on the development of rapid and efficient approaches for their generation mandatory. The rational design of synthetic cycfic peptide analogs, focused on biological activities that imitate natural structural motifs (turns, hefices, etc.), can help to increase their native properties and to adapted them for human applications, for example, in medicine [12-14]. 

Conformational analysis can be performed using a variety of methods.1161 Most important are X-ray analysis and NMR spectroscopic techniques, which allow detailed insights into the topology of the peptides. NMR combined with molecular dynamic calculations provides the spatial structure of the peptide, but also its dynamics in solution.13643491 Additional information can be obtained from FTIR,15,4521 CD,151,53-551 or Raman spectroscopy. 56,571 The results derived from such conformational analysis of cyclic peptides have a considerable impact on the study of the bioactive conformations of peptides and on the design of cyclic peptides as proteinomimetics.124,58,59,6301... 

Figure 13.11. structure of cyclosporine A, an 11 amino-acid cyclic peptide. Cyclosporine is chemically designated as [R-[R, R -( fj]]-cyclic(L-alanyl-D-alanyl-A/-methyl-L-leucyl-A/-methyl-L-leucyl-A/-methyl-L-valyl-3-hydroxy-A/,4-dimethyl-L-2-amino-6-octenoyl-L-(alpha)-amino-butyryl-A/-methylglycyl-A/-methyl-L-leucyl-L-valyl-A/-methyl-L-leucyl). 

Kemp and McNamara166 designed and synthesized lactam 13 (Scheme 7) to stabilize the backbone conformation of a rare P-tum involving a di-peptide bond found between the (/ +1)- and (/+2)-residues in a few cyclic peptide turns via C (/) C (/+1) cyclization. 67 However, its incorporation into a bioactive peptide has never been reported. 

Preparation of a mimetic of the cyclic peptide jaspamide was reported in 1988. 87 Compound 41 (Scheme 17) was designed to mimic the type-II (1-turn of the peptide, which contained the proposed pharmacophoric phenol and 2-bromoindole functional groups. This analogue displayed interesting insecticidal activity against the tobacco budworm, Heliothis vireseins. 

The sea hare Dolabella auricularia has been the source of the powerful cytotastic and antineoplastic constituents designated as dolastatins [311]. Some of these compounds are thiazole-containing cyclic peptides. They were found in very small quantities in the animal (ca. 1 mg each from 100 Kg), making the isolation and structural elucidation of these peptides exceptionally challenging. A review on the dolastatins, written by G. R. Pettit in 1997, covers the reported literature regarding their isolation, characterization, biological activity, and synthesis [312]. Pettit and coworkers reported the thiazole-containing dolastatins dolastatin 3 (404) [313], 10 (2) [314], and 18 (407) [315]. The most important dolastatin and the most potent antineoplastic and tubulin-inhibitory substance known to date is the unique linear pentapeptide dolastatin 10 (2). 

The design and synthesis of cyclic (3-sheet structures is also covered (Section 13.3).[10] Details of synthetic procedures to obtain the cyclic peptides are described (Section 13.3.1) as are considerations of racemization during synthesis and cyclization (Section 13.3.1.1). The remaining parts of this section deal with characterization of cyclic (3-sheet structures (Section... 

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