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Cyclization of peptides with two chemical bridges affords large scaffold diversities

Abstract

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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Fig. 1: Cyclization of peptides with two chemical bridges.
Fig. 2: Cyclization reagents and reaction efficiency.
Fig. 3: Phage selection of double-bridged peptides.
Fig. 4: Role of chemical bridges.
Fig. 5: Stability of double-bridged peptides.
Fig. 6: Double-bridged peptides selected against IL-17.

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Acknowledgements

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

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Contributions

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.

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Correspondence to Christian Heinis.

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

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Supplementary information

Supplementary Information

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

Reporting Summary

Supplementary Slide Show

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

Supplementary Slide Show

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

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Kale, S.S., Villequey, C., Kong, XD. et al. Cyclization of peptides with two chemical bridges affords large scaffold diversities. Nature Chem 10, 715–723 (2018). https://doi.org/10.1038/s41557-018-0042-7

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