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Diverse backbone-cyclized peptides via codon reprogramming

Nature Chemical Biology volume 5, pages 888–890 (2009)Cite this article

Abstract

We report a methodology for the ribosomal synthesis of backbone-cyclized peptides involving genetic code reprogramming to introduce one or more nonproteinogenic amino acids. Expression of linear peptides bearing a cysteine-proline dipeptide sequence followed by glycolic acid results in self-rearrangement to a C-terminal diketopiperadine-thioester, which non-enzymatically generates a cyclized peptide. We demonstrate the ribosomal synthesis of several naturally occurring backbone-cyclized peptides and a library based on a bicyclic scaffold, and we identify bioactive sequences by screening and deconvolution.

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Figure 1: Ribosomal expression of backbone-cyclic peptides.
Figure 2: One-pot expression of RTD-1, its N-methylated analog RTDMe, and SFTI-1.

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Acknowledgements

This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (16101007) and a research and development project of the Japanese Industrial Science and Technology Program in the New Energy and Industrial Technology Development Organization (NEDO) to H.S. T.K. and A.O. are supported by JSPS Research Fellowships for young scientists (20-664 and 19-1722, respectively).

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Author notes

  1. Takashi Kawakami and Atsushi Ohta: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Takashi Kawakami, Atsushi Ohta, Hiroshi Ashigai & Hiroaki Suga

  2. Department of Advanced Interdisciplinary Studies, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Masaki Ohuchi & Hiroaki Suga

  3. Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    Hiroshi Murakami & Hiroaki Suga

Authors
  1. Takashi Kawakami
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  2. Atsushi Ohta
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  3. Masaki Ohuchi
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  4. Hiroshi Ashigai
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  6. Hiroaki Suga
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Contributions

T.K., A.O. and H.S. designed the project. T.K., A.O., M.O., H.A. and H.M. performed experiments. The manuscript was written by T.K., A.O. and H.S.

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Correspondence to Hiroaki Suga.

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Kawakami, T., Ohta, A., Ohuchi, M. et al. Diverse backbone-cyclized peptides via codon reprogramming. Nat Chem Biol 5, 888–890 (2009). https://doi.org/10.1038/nchembio.259

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