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  • Review Article
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Non-symmetric stapling of native peptides

Nature Reviews Chemistry (2024)Cite this article

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Abstract

Stapling has emerged as a powerful technique in peptide chemistry. It enables precise control over peptide conformation leading to enhanced properties such as improved stability and enhanced binding affinity. Although symmetric stapling methods have been extensively explored, the field of non-symmetric stapling of native peptides has received less attention, largely as a result of the formidable challenges it poses — in particular the complexities involved in achieving the high chemo-selectivity and site-selectivity required to simultaneously modify distinct proteinogenic residues. Over the past 5 years, there have been significant breakthroughs in addressing these challenges. In this Review, we describe the latest strategies for non-symmetric stapling of native peptides, elucidating the protocols, reaction mechanisms and underlying design principles. We also discuss current challenges and opportunities this field offers for future applications, such as ligand discovery and peptide-based therapeutics.

Key points

  • Peptide conformation has a crucial role for its functions.

  • Non-symmetric stapling of native peptides constrains peptide conformation by covalently crosslinking two different natural residue side chains within peptides.

  • Non-symmetric stapling can be achieved with high chemo-selectivity and site-selectivity through directing strategy or cooperative strategy.

  • Non-symmetric stapling of native peptides holds great potential for peptide-based therapeutics.

  • The field of non-symmetric stapling of native peptides is still in its early stages with many opportunities for improvement.

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Fig. 1: Overview of non-symmetric stapling of native peptide.
Fig. 2: Strategies for non-symmetric Cys–Lys stapling.
Fig. 3: Stepwise strategies for non-symmetric Cys–Lys stapling.
Fig. 4: Strategies for non-symmetric Cys–Met and Cys–Trp stapling.
Fig. 5: Strategies for non-symmetric Lys–Tyr and Lys–Arg stapling.
Fig. 6: Strategies for non-symmetric Lys–Glu and Lys–Asp stapling.
Fig. 7: Nonspecific non-symmetric stapling through a ‘two birds with one stone’ strategy.

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Acknowledgements

The authors gratefully acknowledges the grant support from Fuzhou University (no. 511264), the National Natural Science Foundation of China (no. 82074005) and Fujian University of Traditional Chinese Medicine (no. X2021008-rencai).

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  1. These authors contributed equally: Fa-Jie Chen, Wanzhen Lin.

Authors and Affiliations

  1. College of Chemistry, Fuzhou University, Fuzhou, P. R. China

    Fa-Jie Chen & Fen-Er Chen

  2. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, P. R. China

    Wanzhen Lin

  3. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, P. R. China

    Fen-Er Chen

  4. Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, Fudan University, Shanghai, P. R. China

    Fen-Er Chen

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F.-J.C. and W.L. contributed equally to the preparation of this manuscript. F.-J.C. and W.L. contributed to the discussion of content, researching data for the article, and writing and editing of the manuscript. F.-E.C. contributed to the discussion of content and reviewing and editing of the manuscript before submission.

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Chen, FJ., Lin, W. & Chen, FE. Non-symmetric stapling of native peptides. Nat Rev Chem (2024). https://doi.org/10.1038/s41570-024-00591-5

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