{
  "abstract": "Innate immune signaling is a double-edged sword: uncontrolled activation drives autoinflammatory diseases, while controlled activation enhances antiviral and antitumor immunity. MDA5, a cytosolic dsRNA sensor that activates type I interferon signaling, mediates both immunopathology and protective immunity, yet small-molecule modulators have remained elusive. Here we report MA2, a first-in-class selective MDA5 agonist that acts as a molecular glue. MA2 binds a cryptic inter-protomer pocket within MDA5 filaments that undergoes ATPase-associated conformational remodeling. Rather than rigidly locking the interface, MA2 remains bound while accommodating and reshaping these structural transitions, strengthening MDA5-dsRNA and inter-protomer interactions and attenuating ATP hydrolysis. MA2 does not induce new filament assembly but potentiates pre-existing filaments, enabling context-dependent activation in dsRNA-enriched cells. MA2 enhances antiviral activity and synergizes with chemotherapeutic agents and natural killer cells to promote tumor cell killing. These findings establish dynamic molecular glues as a strategy for targeting conformationally plastic interfaces previously considered undruggable.",
  "abstract_shown": true,
  "affiliations": [
    "Boston Children's Hospital"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "S. Hur"
    },
    {
      "name": "L. Yan"
    },
    {
      "name": "Z. Ye"
    },
    {
      "name": "Z. Li"
    },
    {
      "name": "S. Pokharel"
    },
    {
      "name": "T. Y.-T. Hsu"
    },
    {
      "name": "C. Torres-Arancivia"
    },
    {
      "name": "K. Haratani"
    },
    {
      "name": "E. Ivanova"
    },
    {
      "name": "C. Paweletz"
    },
    {
      "name": "S. Cherry"
    },
    {
      "name": "D. Barbie"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/degk26rtad9x9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.14.759171",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1.full",
  "id": "degk26rtad9x9",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7223045366",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/degk26rtad9x9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:46Z",
      "native_id": "10.64898/2026.10.14.759171",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity",
  "title_text": "A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:46Z",
  "url": "https://research.draconitic.com/paper/degk26rtad9x9",
  "venue": "bioRxiv",
  "versions": []
}