{
  "abstract": "Interleukin-23 (IL-23) drives T-helper-17 inflammation underlying inflammatory bowel disease and psoriasis; anti-p19 antibodies are clinically effective but large, costly, and injectable. De novo miniproteins are an attractive alternative, yet published designs target the IL-23 receptor; the IL-23 cytokine itself has not been addressed. A further obstacle is that the standard confidence score (ipTM) tracks construct length rather than interface quality. We computationally design miniprotein binders against the IL-23R-binding face of p19 (PDB 3DUH) and score every design with ipSAE, a length-robust interface metric derived from AlphaFold-initial-guess predicted aligned error. A conventional RFdiffusion/ProteinMPNN/ColabFold pipeline yields no reliable predicted interface across 972 designs (best ipSAE 0.30), and a scoring artifact, in which single-sequence ColabFold under-rates binder pLDDT by approximately 56 points, explains an earlier misleading \"binders do not fold\" signal. An interface-optimized hallucination method (BindCraft), scored identically, yields 42 of 50 designs above ipSAE 0.60 (best 0.804). An AlphaFold-independent geometric check reproduces the conventional failure: no top-ranked conventional design reaches the buried area or interface hydrogen-bond count of the weakest lead. Five all-alpha-helical leads (72-104 residues) collectively engage all six targeted hotspots; two dock within the intact p40/p19 heterodimer and all show favorable Rosetta energetics. A p40-alone counter-screen returns ipSAE 0.00 for all five, indicating no spurious p40 interface. To our knowledge, these are the first computationally proposed de novo miniprotein candidates designed to occlude the IL-23R-binding face of IL-23 p19. All results require experimental validation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": "2610.32779",
  "author_total": 2,
  "authors": [
    {
      "name": "Raghav Paladugu"
    },
    {
      "name": "Fardina Fathmiul Alam"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/478dczj66c38k.bib",
  "cited_by": 0,
  "doi": "10.48550/arxiv.2610.32779",
  "fulltext_url": null,
  "id": "478dczj66c38k",
  "issns": [],
  "landing_url": "https://arxiv.org/abs/2610.32779",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": "CC0-1.0",
  "native_subjects": [
    [
      "arxiv",
      "cs.LG"
    ],
    [
      "arxiv",
      "q-bio.BM"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7223708854",
  "pdf_url": "https://arxiv.org/pdf/2610.32779",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/478dczj66c38k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:35:44Z",
      "native_id": "2610.32779",
      "source": "arxiv",
      "url": "https://arxiv.org/abs/2610.32779"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "arxiv:q-bio.BM",
      "subfield": "biophysics"
    }
  ],
  "title": "Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19",
  "title_text": "Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19",
  "type": "preprint",
  "updated_at": "2026-10-30T12:35:44Z",
  "url": "https://research.draconitic.com/paper/478dczj66c38k",
  "venue": "arXiv",
  "versions": []
}