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Peer-reviewedCC BYNature Chemical Biology

Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction

  • Xinjian Ji1
  • Lluc Farrera Soler1
  • Jiajun Li1
  • Gontran Sangouard1
  • Nathan De Sadeleer1
  • Alexander L. Nielsen1
  • Mothukuri Ganesh Kumar1
  • Anne Zarda1
  • E.J. Will1
  • Florence Pojer2
  • Kelvin Lau2
  • Christian Heinis3
  1. 1Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
  2. 2Protein Production and Structure Core Facility (PTPSP), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
  3. 3Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. [email protected]
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Abstract

Small, nonpolar cyclic peptides can both bind challenging targets and cross cell membranes, making them attractive for addressing currently undruggable targets such as many protein-protein interactions (PPIs). However, developing such compounds de novo without prior information about lead structures such as natural ligands or fragments remains a notable challenge. Here we show that functional screening of structurally highly diverse cyclic peptide libraries synthesized at nanomole scale allows identification of sub-kDa inhibitors of a PPI. By screening 15,360 fully random cyclic peptides, we were able to identify an inhibitor of the E3 ligase adaptor Keap1 and its substrate Nrf2. Optimization by rapid design-build-test cycles produced a membrane-permeable compound active in live cells. This study demonstrates that large, diverse cyclic peptide libraries can enable the discovery of cell-permeable PPI inhibitors from the ground up, providing a way to harness the powerful modality of small cyclic peptides to address often difficult-to-target intracellular interactions.

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Cite

BibTeXRIS
BibTeX
@article{ji2026generation,
  title = {{Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction}},
  author = {Xinjian Ji and Lluc Farrera Soler and Jiajun Li and Gontran Sangouard and Nathan De Sadeleer and Alexander L. Nielsen and Mothukuri Ganesh Kumar and Anne Zarda and E.J. Will and Florence Pojer and Kelvin Lau and Christian Heinis},
  journal = {Nature Chemical Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41589-026-02237-7},
  url = {https://doi.org/10.1038/s41589-026-02237-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction
AU  - Xinjian Ji
AU  - Lluc Farrera Soler
AU  - Jiajun Li
AU  - Gontran Sangouard
AU  - Nathan De Sadeleer
AU  - Alexander L. Nielsen
AU  - Mothukuri Ganesh Kumar
AU  - Anne Zarda
AU  - E.J. Will
AU  - Florence Pojer
AU  - Kelvin Lau
AU  - Christian Heinis
PY  - 2026
DA  - 2026/06/01
JO  - Nature Chemical Biology
DO  - 10.1038/s41589-026-02237-7
UR  - https://doi.org/10.1038/s41589-026-02237-7
AB  - Small, nonpolar cyclic peptides can both bind challenging targets and cross cell membranes, making them attractive for addressing currently undruggable targets such as many protein-protein interactions (PPIs). However, developing such compounds de novo without prior information about lead structures such as natural ligands or fragments remains a notable challenge. Here we show that functional screening of structurally highly diverse cyclic peptide libraries synthesized at nanomole scale allows identification of sub-kDa inhibitors of a PPI. By screening 15,360 fully random cyclic peptides, we were able to identify an inhibitor of the E3 ligase adaptor Keap1 and its substrate Nrf2. Optimization by rapid design-build-test cycles produced a membrane-permeable compound active in live cells. This study demonstrates that large, diverse cyclic peptide libraries can enable the discovery of cell-permeable PPI inhibitors from the ground up, providing a way to harness the powerful modality of small cyclic peptides to address often difficult-to-target intracellular interactions.
SN  - 1552-4450
SN  - 1552-4469
ER  -