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Synthesis of N-methylated cyclic peptides

Nature Protocols volume 7, pages 432444 (2012) | Download Citation

Abstract

This protocol presents a detailed description of the synthesis of N-methylated cyclic peptides. N-methylation is a powerful technique to modulate the physicochemical properties of peptides by introducing one or more methyl groups into the peptidic amide bonds. Together with peptide cyclization, this procedure confers unprecedented pharmacokinetic properties to the peptides, including metabolic stability, membrane permeability and even oral bioavailability. Here we describe two simplified methods of N-methylation of linear peptides on solid supports, which can be performed in less than 2 h and are applicable to any amino acid. Finally, we also describe two methods of peptide cyclization, which can be used to obtain the N-methylated cyclic peptide and which are not limited to specific peptide sequences. With this protocol, multiply N-methylated cyclic peptides can be synthesized in as little as 4–5 d.

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Acknowledgements

We thank M.M. Baksh of the Scripps Research Institute for his help in proofreading and editing the manuscript.

Author information

Author notes

    • Horst Kessler

    Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. Present addresses: European Molecular Biology Laboratory, Heidelberg, Germany (J.C.); Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA (B.L.).

Affiliations

  1. Institute for Advanced Study and Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Garching, Germany.

    • Jayanta Chatterjee
    • , Burkhardt Laufer
    •  & Horst Kessler

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Contributions

J.C. and B.L. conducted the experiments as reported in the original papers and tested the protocol. H.K. supervised the overall project. J.C. wrote the manuscript, B.L. and H.K. edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Horst Kessler.

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DOI

https://doi.org/10.1038/nprot.2011.450

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