{
  "abstract": "Ion channels remain notoriously recalcitrant drug targets despite their extensive pathophysiological significance. Acid-sensing ion channels (ASICs) are proton-gated cation channels that cause neuronal death when excessively activated, such as during ischaemic stroke. This acidosis-driven injury pathway remains unchallenged by existing therapeutics. Here we generate two de novo designed hASIC1a-specific miniproteins by developing a platform that integrates computational miniprotein design, high-throughput automated patch clamp screening, biophysical and structural characterisation, and in vivo validation. We identify a subtype-selective hASIC1a inhibitor, Denasin1, which achieves near-complete inhibition with nanomolar potency. Denasin1 is disordered in solution but adopts the computationally predicted helix-turn-helix fold when bound to the extracellular acidic pocket of hASIC1a. Crucially, Denasin1 reduces infarct volume by > 50% in a murine model of ischaemic stroke. We thereby establish our de novo design platform as a route to develop potent and selective ion channel modulators.",
  "abstract_shown": true,
  "affiliations": [
    "University of Copenhagen"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "J. Sormann"
    },
    {
      "name": "K. Epitropaki"
    },
    {
      "name": "M. F. Vicino"
    },
    {
      "name": "C. L. Fjorbak"
    },
    {
      "name": "C. F. Pugh"
    },
    {
      "name": "B. Lang"
    },
    {
      "name": "E. K. Beyer"
    },
    {
      "name": "R. Comaposada-Baro"
    },
    {
      "name": "F. Hink"
    },
    {
      "name": "S. Friis"
    },
    {
      "name": "S. G. Usher"
    },
    {
      "name": "C. Cai"
    },
    {
      "name": "H. E. Autzen"
    },
    {
      "name": "J. M. Rogers"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Pless"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2vc7fzf3fet0h.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.04.755611",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1.full",
  "id": "2vc7fzf3fet0h",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7221184992",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2vc7fzf3fet0h.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:45Z",
      "native_id": "10.64898/2026.10.04.755611",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "A deep learning-generated hASIC1a miniprotein inhibitor confers neuroprotection in stroke",
  "title_text": "A deep learning-generated hASIC1a miniprotein inhibitor confers neuroprotection in stroke",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:45Z",
  "url": "https://research.draconitic.com/paper/2vc7fzf3fet0h",
  "venue": "bioRxiv",
  "versions": []
}