Flexibility-tuning of dual-display DNA-encoded chemical libraries facilitates cyclic peptide ligand discovery

Dimitar Petrov, Louise Plais, Kristina Schira, Junyu Cai, Michelle Keller, Alice Lessing, Gabriele Bassi, Samuele Cazzamalli, Dario Neri, Andreas Gloger and Jörg Scheuermann ()
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Dimitar Petrov: ETH Zurich
Louise Plais: ETH Zurich
Kristina Schira: ETH Zurich
Junyu Cai: ETH Zurich
Michelle Keller: ETH Zurich
Alice Lessing: ETH Zurich
Gabriele Bassi: Libernstrasse 3
Samuele Cazzamalli: Libernstrasse 3
Dario Neri: Libernstrasse 3
Andreas Gloger: ETH Zurich
Jörg Scheuermann: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Cyclic peptides constitute an important drug modality since they offer significant advantages over small molecules and macromolecules. However, access to diverse chemical sets of cyclic peptides is difficult on a large library scale. DNA-encoded Chemical Libraries (DELs) provide a suitable tool to obtain large chemical diversity, but cyclic DELs made by standard DEL implementation cannot efficiently explore their conformational diversity. On the other hand, dual-display Encoded Self-Assembling Chemical (ESAC) Libraries can be used for modulating macrocycle flexibility since the two displayed peptides can be connected in an incremental fashion. In this work, we construct a 56 million dual-display ESAC library using a two-step cyclization strategy. We show that varying the level of conformational restraint is essential for the discovery of specific ligands for the three protein targets thrombin, human alkaline phosphatase and streptavidin.

Date: 2025
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DOI: 10.1038/s41467-025-58507-w

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