Can N-methylated amino acids serve as substitutes for prolines in conformational design of cyclic pentapeptides?

The incorporation of proline into cyclic peptides seems to be the most promising way to induce β-turn structures. Recently, however, it was shown that N-methylated amino acids might be even better suited than proline for introducing turn structures. Another property of proline, the ability to effect cis-peptide bonds, has also been reported for N-methylated amino acids. These findings raise the question if it might be possible to replace a proline by an N-methylated amino acid without altering the desired conformational features. The most important benefit of replacing proline by an N-methylated residue is that one recovers the side-chain functionalities, which could be used for enhancing binding selectivity, or to tune a cyclic peptide concerning its pharmacological properties. Here, we compare cyclic peptides containing one or two prolines or N-methylated alanines and a combination of both with respect to preferred conformations and cis-peptide bonds. In addition, the positions have been investigated where an N-alkylated amino acid has to be incorporated to mimic structural aspects usually introduced by proline residues. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.