X‐ray structures of aza‐proline‐containing peptides

Abstract

The aza‐analogue of proline (AzPro) contains a nitrogen atom in place of the CHα of the cognate residue. The resolution of the crystal structures of seven AzPro‐containing peptides, presenting a set of ten AzPro motifs, reveals the structural properties of this particular aza‐residue. Because of sterical hindrances, both nitrogen atoms are out of planarity, and the reduced electronic conjugation in the two AzPro‐adjacent amide groups probably explains the longer amide bond distances and the weak proton‐accepting character of the two pyrazolidine nitrogens. The absolute configuration of both AzPro nitrogens depends on the chemical nature of the sequence. In all cases, the AzPro residue assumes the same intrinsic three‐dimensional structure and presents folding tendencies opposed to those induced by proline.

Three cheers for nitrogen: aza-DKPs, the aza analogues of 2,5-diketopiperazines

“…These modied peptides showed a attening of the spatial arrangement of the substituents linked to the new nitrogen atom while having the potential to exhibit adaptive chirality. 22,23 This structural difference was also observed by us in the comparison between a DKP and its aza-DKP analogue by X-ray crystallography (Fig. 3).…”

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

“…This nitrogen substitution is believed to have little effect on the overall physicochemical profiles of these peptides; however, electronic repulsion between the adjacent nitrogen atoms has been suggested to induce type I and II b-turn conformations. [19][20][21][22][23][24][25][26][27][28][29][30][31] This b-turn geometry of aza amino acid-containing peptides may contribute to improve binding affinity of metastin analogs for KISS1R. NMR analysis of the metastin(45-54) analog in dodecylphosphocholine micelles showed that it contained several tight turn structures such as miscellaneous type IV b-turns (residues Asn 48 -Gly 51 and Gly 51 -Phe 54 ).…”

Peptidomimetics via modifications of amino acids and peptide bonds

“…88,89 This replacement eliminates chirality at the a-position and decreases the electrophilicity of the carbonyl group by altering the geometry of the a position from tetrahedral to trigonal (i.e., planar, achiral), with dihedral angles (j = 901 AE 301 or À901 AE 301, and C = 01 AE 301 or 1801 AE 301) providing b-turn conformations. [90][91][92][93] b-Turn azapeptide conformations have been demonstrated by X-ray crystallography, [94][95][96] spectroscopy, 97,98 and by computational models 90,92,93 (Fig. 9).…”