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Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery

Nature Reviews Chemistry volume 4, pages 90–101 (2020)Cite this article

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Abstract

Drug discovery has traditionally focused on using libraries of small molecules to identify therapeutic drugs, but new modalities, especially libraries of genetically encoded cyclic peptides, are increasingly used for this purpose. Several technologies now exist for the production of libraries of cyclic peptides, including phage display, mRNA display and split-intein circular ligation of peptides and proteins. These different approaches are each compatible with particular methods of screening libraries, such as functional or affinity-based screening, and screening in vitro or in cells. These techniques allow the rapid preparation of libraries of hundreds of millions of molecules without the need for chemical synthesis, and have therefore lowered the entry barrier to generating and screening for inhibitors of a given target. This ease of use combined with the inherent advantages of the cyclic-peptide scaffold has yielded inhibitors of targets that have proved difficult to drug with small molecules. Multiple reports demonstrate that cyclic peptides act as privileged scaffolds in drug discovery, particularly against ‘undruggable’ targets such as protein–protein interactions. Although substantial challenges remain in the clinical translation of hits from screens of cyclic-peptide libraries, progress continues to be made in this area, with an increasing number of cyclic peptides entering clinical trials. Here, we detail the various platforms for producing and screening libraries of genetically encoded cyclic peptides and discuss and evaluate the advantages and disadvantages of each approach when deployed for drug discovery.

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Fig. 1: Biopanning of a phage-display library.
Fig. 2: Methods for the generation of bicyclic peptides displayed on bacteriophages.
Fig. 3: Overview of mRNA display.
Fig. 4: Generating cyclic peptides for mRNA display.
Fig. 5: The mechanism of cyclic-peptide production by SICLOPPS.
Fig. 6: The bacterial reverse two-hybrid system.

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Acknowledgements

A.T. thanks Cancer Research UK (A20185) for support.

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  1. School of Chemistry, University of Southampton, Southampton, UK

    Catrin Sohrabi & Ali Tavassoli

  2. Curve Therapeutics, University of Southampton, Southampton, UK

    Andrew Foster & Ali Tavassoli

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A.T. and A.F. are employees and shareholders of Curve Therapeutics. C.S is a shareholder in Curve Therapeutics.

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Sohrabi, C., Foster, A. & Tavassoli, A. Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery. Nat Rev Chem 4, 90–101 (2020). https://doi.org/10.1038/s41570-019-0159-2

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