{
  "abstract": "Transcription factor protein interactions remain among the most challenging targets in chemical biology, particularly those driven by leucine zipper coiled coil assemblies. For this challenge we developed a peptide-directed ligand design strategy identifying inhibitors of the Nrf2/MafG transcription factor complex, a key driver of cytoprotective signalling and cancer chemoresistance. MafG-derived α-helical peptides bind Nrf2 and disrupt formation of the Nrf2/MafG/DNA complex. Guided by structural modelling, peptide-small molecule hybrids were subsequently developed that preserved inhibitory activity while reducing peptide content. Lead hybrids inhibited Nrf2/MafG/DNA assembly, suppressed Nrf2-dependent transcriptional responses, reduced HO-1 and NQO1 gene expression, NQO1 enzymatic activity, and decreased nuclear localisation of Nrf2 in A549 cells. Disruption of Nrf2/MafG signalling restored sensitivity to gemcitabine in an intrinsically chemoresistant lung cancer model. This provides a new approach for the modulation of coiled-coil transcription factor interactions and new chemical probes for Nrf2-dependent chemoresistance in cancer biology.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Ellen E. Hyde"
    },
    {
      "name": "Emily Hobson"
    },
    {
      "name": "Owen Mullen"
    },
    {
      "name": "Zoë R. Goddard"
    },
    {
      "name": "Sean Tattan"
    },
    {
      "name": "Marco M.D. Cominetti"
    },
    {
      "name": "Mark Searcey"
    },
    {
      "name": "Maria A. O’Connell"
    },
    {
      "name": "Andrew M. Beekman",
      "orcid": "0000-0002-3056-6406"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8c8zyxx5dws8s.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009846/v1",
  "fulltext_url": null,
  "id": "8c8zyxx5dws8s",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009846/v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics, phytochemicals, and oxidative stress"
    ]
  ],
  "openalex": "W7220454537",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009846/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/8c8zyxx5dws8s.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:22Z",
      "native_id": "10.26434/chemrxiv.15009846",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009846/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics, phytochemicals, and oxidative stress",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.",
  "title_text": "Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:22Z",
  "url": "https://research.draconitic.com/paper/8c8zyxx5dws8s",
  "venue": "ChemRxiv",
  "versions": []
}