Cis peptide

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. 

While the trans peptide linkage shown in Fig. 2-4 is usual, the following cis peptide linkage, which is 8 kj/mol less stable than the trans linkage, also occurs in proteins quite often. The nitrogen atom is usually but not always from proline.81 84... 

An ester linkage joins the methylvaline residue of the peptide to the side-chain hydroxyl of threonine. Two cis peptide linkages are present. Ignoring the obvious asymmetry of the phenoxazine ring, actinomycin possesses approximate twofold symmetry. 

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.

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