Peptide bond cyclic stabilization

Cyclosporin A contains II amino acids, joined in a cyclic strncture by peptide bonds. The structure is also stabilized by intramolecular hydrogen bonds. Only two of the amino acids, i.e. alanine and valine, are typical of proteins. The compound contains several A-methylated amino acid residues, together with the even less common L-a-aminobutyric acid and an Ai-methylated butenylmethylthreonine. There is one o-amino acid, i.e. o-alanine, and the assembly of the polypeptide chain is known to start from this residue. Many of the other natural cyclosporin structures differ only with respect to a single amino acid (the a-aminobutyric acid residue) or the number of amino acids that have the extra Ai-methyl group. 

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. 

Fig. 3. (a) Chemical structure of a synthetic cyclic peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the flat rings are hydrophobic and allow insertion into lipid bilayers, (b) Proposed structure of a self-assembled transmembrane pore comprised of hydrogen bonded cyclic peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in lipid bilayers (71). 

Cydo-fSarg) (70) was subjected to further invest ations and was proved to assume the same conformation in crystalline state as in solution, where the peptide bond had a cis-cis-trans-tramtrans-trans sequence. As stated earlier, in cyclic peptides made of N-unsubstituted amino acids, formation of the tum accompanied with intramolecular hydrogen bonds contributes to the stabilization of the ringstruc-... 

In the right-handed a-helix, the peptide chain forms a helix (like a cork screw) with the side groups on the outside, where each turn takes 3.6 residues (18 residues making 5 turns) the translation of the helix is 0.15 nm per residue (i.e., a pitch of 0.54 nm per turn), compared to 0.36 nm per residue for a stretched chain (Figure 7.2). The helical conformation is stabilized by H-bonds, between the O of peptide bond i and the NH of peptide bond i + 4. Moreover, enhanced van der Waals attraction is involved. The possibility for the latter to occur varies among amino acid residues, which means that not all of them readily partake in an a-helix. Ala, Glu, Phe, His, lie, Leu, Met, Gin, Val, and Trp have strong tendencies to form helices, whereas Pro, owing to its cyclic structure, is a helix breaker. ... 

Conceptually, the amino and carboxyl termini of a polypeptide chain are flexible and amendable to form a peptide bond. The formation of the terminally linked peptide bond yields circular (cyclic) proteins with circular backbones. Cyclic peptides such as cyclosporin are known. These peptides tend to be less than 12 amino acids in size, contain modifled amino acids and are generally metabolic products. Whereas circular proteins are 14-70 amino acids in size, true gene products (encoded by DNA) with well-defined 3D structures. They occur in microorganisms, plants and animals, as products for an enhanced stability or involvement in host defense (Trabi and Craik, 2002). Several naturally occurring circular proteins are listed in Table 5.10. CyBase (http //research.imb.uq.edu.au/ cybase) is the curated database for cyclic proteins. 

We have indicated earlier that there is an alternative possible explanation for the existence of apparently strong peptide bonds and proteolytic explosion in terms of cyclic structures. Even in the absence of stabilizing hydrogen bonds, the peptide bond in a cyclic structure would appear stronger because its hydrolysis would not lead to the formation of new fragments with an accompanying increase in entropy. However, the sub-... 

The influence of backbone flexibility was seen, for example, when the stability of the linear tetrapeptide 6.70 was compared to that of a cyclic hexa-peptide derivative of the same sequence [91]. Indeed, the cyclic peptide was approximately one order of magnitude more stable than the linear peptide in the pH range of 2-7. The results at higher pH values were inconclusive since the stability of the cyclic peptide decreased dramatically due to the degradation of a disulfide bond absent in the linear peptide. 

The other simple peptide complex e.g. [Fe(Z-Cys-Ala-OMe)4]2- did not exhibit such a reversible redox couple under similar conditions. The Fe(lll) complexes of simple peptide thiolates or cysteine alkyl esters are found to be thermally quite unstable and decompose by oxidaticxi at the thiolate ligand by intramolecular electron transfer. Thus the macro-ring chelation of the Cys-Pro-Leu-Cys ligand appears to stabilize the Fe(in) state. The stability of the Fe(ni) form as indicated by the cyclic voltamnoogram measurements and by the visible spectra of the Fe(in) peptide complexes suggests that the peptide prevents thermal and hydrolytic decomposition of the Fe-S bond because of the hydrophobicity and steric bulk of the Pro and Leu residues (3,4). 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

The steric bulk of the thioamide sulfur results in conformational changes that have been documented in cyclopentapeptide and cyclohexapeptide model systems (for more details see Vol. E22b, Section 6.8.5.2.1). For example, in c[-Proi(>[C(=S)-NH]Gly-Pro-Gly-D-Phe-], the first synthetic cyclic thiopeptide, an intramolecular y-turn seen in the all-amide parent compound by NMR methods was perturbed by the putative interaction of sulfur with the adjacent Pro s (3-protons.[9 On the other hand, in a cyclic hexapeptide, the enhanced H-bond donor capacity of the thioamide NH led to the formation of a relatively strong intramolecular H-bond stabilized (3-turn, which was frame shifted compared to that found in its all-amide parent peptide. 10 ... 

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