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

Authors

  • Burkhardt Laufer,

    1. Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching, D-85747 Germany
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  • Jayanta Chatterjee,

    1. Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching, D-85747 Germany
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  • Andreas O. Frank,

    1. Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching, D-85747 Germany
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  • Horst Kessler

    Corresponding author
    1. Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching, D-85747 Germany
    • Department Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching, D-85747 Germany.
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  • 11th Naples Workshop on Bioactive Peptides

Abstract

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.

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