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Cyclization of peptides with two chemical bridges affords large scaffold diversities

Nature Chemistryvolume 10pages715723 (2018) | Download Citation


Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema. These libraries yielded inhibitors with remarkable binding properties (subnanomolar Ki, >1,000-fold selectivity) despite the small molecular mass (~1,200 Da). An interlaced bridge format characteristic of this strategy provided high proteolytic stability (t1/2 in plasma of >3 days), making double-bridged peptides potentially amenable to topical or oral delivery.

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This work was supported by the NCCR Chemical Biology of the Swiss National Science Foundation.

Author information

Author notes

  1. These authors contributed equally: Sangram S. Kale, Camille Villequey, Xu-Dong Kong.


  1. Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    • Sangram S. Kale
    • , Camille Villequey
    • , Xu-Dong Kong
    • , Alessandro Zorzi
    • , Kaycie Deyle
    •  & Christian Heinis


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S.S.K., C.V., X.-D.K. and C.H. conceived the strategy, designed experiments, analysed data and wrote the manuscript. S.S.K. established the chemical reactions. C.V. and X.-D.K. performed the phage selections. S.S.K., C.V. and X.-D.K. synthesized, purified and characterized peptides. A.Z. synthesized a linker reagent. K.D. contributed to the writing of the manuscript. S.S.K., C.V. and X.-D.K. contributed equally to this work.

Competing interests

C.H. is a scientific founder of Bicycle Therapeutics. All other authors declare no competing interests.

Corresponding author

Correspondence to Christian Heinis.

Supplementary information

  1. Supplementary Information

    Supplementary Materials and Methods, Tables 1–3, and Figures 1–13

  2. Reporting Summary

  3. Supplementary Slide Show

    An animated slide show illustrating graphically the large scaffold diversity that can be generated

  4. Supplementary Slide Show

    An animated slide show illustrating graphically the large scaffold diversity that can be generated

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