Cis-Peptide bond

Examlnatloi of molecular models revealed that the desired two B-tum conformation might be restored by moving the N-methyl group from D-Ala to D-Phell in 4. This change would permit the key cis peptide bond to form in the proper location in the backbone and should as a result achieve better overall side chain correspondence with 3b. The resultant structure, cyclo- (N -Me-D-Phe-D-Thr-D-Lys-L-Trp-D-Phe-D-Ala) 5, was prepared and in fact, displayed a full biological response and had about 10) of the potency of 3b and 25 of somatostatin Itself. 

Scheme 28 Formation of Piperazine-2,5-diones via a cis Peptide Bond Isomer...

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Scheme 1 The Use of Aromatic Rings to Enforce the trans or cis Peptide Bond...

Aminomethyl)pyrrole-2-carboxylic acid (85, Scheme 24) was used with good results as a spacer in the synthesis of cyclic peptide GPIIb/IIIa receptor antagonists.[74 The 1,2-sub-stituted pyrrole 8 represents a cis peptide bond surrogate in which the R1 side chain can easily be varied. However, no application in biologically relevant peptides have been reported to date. 

The synthesis of the cis peptide bond surrogate 8 is shown in Scheme 25J4 ... 

HELIX, SHEET, TURN, CISPEP, and SITE lines, listing the elements of secondary structure in the protein, residues involved in cis-peptide bonds (almost always involving proline as the second residue), and residues in the active site of the protein. 

Figure 6. Stereogram of the metal ions and carbohydrate binding regions. The backbone atoms from Glu 8 to Asp 19 and from Ser 203 to Ala 11 plus designated side chains. The cis peptide bond is between Ala 207 and Asp 208, producing a distinct kink in this strand of /3-sheet.

Figure 7. The polypeptide backbone from Lys 200 (top-right) to Phe 213. The carbohydrate binding position is represented by the stick drawing of aMeMan. The cis peptide bond is the first peptide bond to the left of Pro 206 (see Figure 6 for the residue numbers).

Figure 1 (Left) Model of the receptor-bound conformation of TIP containing all-trans peptide bonds (heavy lines) in spatial overlap with naltrindole (light lines). (Right) Model of the receptor bound conformation of H-Tyr-Tic-NH2 containing a cis peptide bond (heavy lines) in spatial overlap with naltrindole (light lines). In both cases the N-terminal amino group and the Tyr1 and Tic2 aromatic rings of the peptide are superimposed on the corresponding pharmacophoric moieties in the alkaloid structure.

In addition to the order-disorder transition, observed for a helices, helical structures can also be induced to undergo transitions from one ordered form to another. For example, a crystalline form of poly[p-(p-chlorobenzyl)-L-aspartate] can be made to undergo a phase transition from an a-helical to an co-helical form by heating rotational entropy is computed to play a role in this process.68 Another order-order transition is the solvent-induced interconversion between polyproline 1 (with cis peptide bonds) and polyproline 11 (with trans peptide bonds), a process that has also been subjected to conformational energy calculations.85 The transition has been accounted for in terms of differences in the binding of solvent components to the peptide 0=0 groups. 

Peptide bonds are planar and can be either in the trans or in the cis conformation with respect to the two successive C positions. These conformations are equivalent to dihedral angles trans state is strongly favored for peptide bonds that do not involve proline residues. The cis conformation has not been detected in unstructured, linear oligopeptides, and the equilibrium population of the cis form is believed to be less than 0.1% (Brandts et al., 1975, Jorgensen and Gao, 1988). Very few nonproline cis peptide bonds have been found in native, folded proteins by X-ray crystallography (Stewart et al, 1990 MacArthur and Thornton, 1991). 

On the other hand, the addition of benzene to the chloroform solution of Cyclo-(Sar2) and Cyclo-(Sar ly) caused upfield shifts of N-CH3 and resonance signals (77), although these cyclic peptides only have a cis peptide bond. The upfield shift implies the complex formation between the cyclic peptides and benzene. However, this complex may have been formed due to a dipole-induced dipole interaction, the latter being generated in benzene by the ac tiDn of a strong dipole of cyclic peptides. A/[tenzene], in which A represents the benzene-induced ft in ppm, was... 

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