{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland",
    "Protein Production and Structure Core Facility (PTPSP), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland",
    "Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. christian.heinis@epfl.ch"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xinjian Ji",
      "orcid": "0000-0003-1969-7373"
    },
    {
      "affs": [
        0
      ],
      "name": "Lluc Farrera Soler",
      "orcid": "0000-0002-3403-6357"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiajun Li",
      "orcid": "0000-0003-1829-3027"
    },
    {
      "affs": [
        0
      ],
      "name": "Gontran Sangouard",
      "orcid": "0000-0003-1258-9636"
    },
    {
      "affs": [
        0
      ],
      "name": "Nathan De Sadeleer",
      "orcid": "0000-0001-8265-9359"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexander L. Nielsen",
      "orcid": "0000-0003-1195-0143"
    },
    {
      "affs": [
        0
      ],
      "name": "Mothukuri Ganesh Kumar",
      "orcid": "0000-0001-5529-8447"
    },
    {
      "affs": [
        0
      ],
      "name": "Anne Zarda",
      "orcid": "0000-0001-8123-8771"
    },
    {
      "affs": [
        0
      ],
      "name": "E.J. Will",
      "orcid": "0000-0003-4768-692X"
    },
    {
      "affs": [
        1
      ],
      "name": "Florence Pojer",
      "orcid": "0000-0002-9183-7206"
    },
    {
      "affs": [
        1
      ],
      "name": "Kelvin Lau",
      "orcid": "0000-0002-9040-7597"
    },
    {
      "affs": [
        2
      ],
      "name": "Christian Heinis",
      "orcid": "0000-0001-9982-9457"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ajqv2sn8dkwf9.bib",
  "cited_by": 7,
  "doi": "10.1038/s41589-026-02237-7",
  "fulltext_url": null,
  "id": "ajqv2sn8dkwf9",
  "issns": [
    "1552-4450",
    "1552-4469"
  ],
  "landing_url": "https://doi.org/10.1038/s41589-026-02237-7",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Chemical Synthesis and Analysis"
    ],
    [
      "openalex",
      "1605|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7163052933",
  "pdf_url": null,
  "pmcid": "PMC13661285",
  "pmid": "42225940",
  "published": "2026-06-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/ajqv2sn8dkwf9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W7163052933",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41589-026-02237-7"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
    },
    {
      "field": "chemistry",
      "origin": "openalex:1605|Chemical Synthesis and Analysis",
      "subfield": "organic"
    }
  ],
  "title": "Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction",
  "title_text": "Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:25Z",
  "url": "https://research.draconitic.com/paper/ajqv2sn8dkwf9",
  "venue": "Nature Chemical Biology",
  "versions": []
}