Prolinoamino acids as tools to build bifunctionalized, stable beta-turns in water.

The design of peptidomimetics able to mimic the structural and binding motifs of proteins is a major challenge in the development of new pharmaceutical tools. The b-turn motif is one of the major secondary structure elements that plays an important role in the folding of globular proteins and is often implicated as a recognition element in receptor–ligand interactions. Considerable effort has been devoted to the development of synthetic templates as reverse turn mimics. One strategy consists in restricting the conformational space of the central positions by means of bior tricyclic rings. A second approach is based on stabilizing the Nand C-terminal residues by covalent bridging or folding through noncovalent cation–p interactions. Another strategy to stabilize b-turn conformations is the incorporation of proline residues that are known to have a high b-turn propensity. Heterochiral d-Pro-l-Pro or l-Pro-d-Pro sequences adopt types II’ or II b-turn conformations, respectively. The replacement of one proline residue by an N-methyl amino acid (d-Pro-l-NMeXaa or l-Pro-d-NMeXaa sequences) further stabilizes the b-turn conformation and enables the introduction of a side chain functionality in the i+2 position of the b-turn. We have explored the possibility of recovering the side chain functionality in the i+1 position using cis-3-substituted prolinoamino acids (P3Xaa). [7] These prolinoamino acids, which are easily accessible by chemical synthesis when not commercially available, can be considered as chimeras between proline and a proteinogenic amino acid. The conformational constraint of the pyrrolidine template limits the conformational space around the f and c torsion angles. Prolinoamino acids can have applications as conformational tools for probing the bioactive conformations of peptides and for pharmaceutical use. We have previously introduced a cis-3-prolinoleucine (P3Leu) in the Piv-d-P c 3Leu-l-Pro-NHMe sequence and shown that this short peptide bearing the side chain of Leu in the i+1 position adopts a stable b-turn structure in organic solvents and in water. In this study, we have validated the use of prolinoamino acids in Piv-d-P3Xaa-l-NMeYaa-NHMe sequences (Scheme 1) to stabilize short b-turns, in water, that possess the two side