A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity

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.

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BibTeX RIS

BibTeX

@misc{hur2026dynamic,
  title = {{A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity}},
  author = {S. Hur and L. Yan and Z. Ye and Z. Li and S. Pokharel and T. Y.-T. Hsu and C. Torres-Arancivia and K. Haratani and E. Ivanova and C. Paweletz and S. Cherry and D. Barbie},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.14.759171},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity
AU  - S. Hur
AU  - L. Yan
AU  - Z. Ye
AU  - Z. Li
AU  - S. Pokharel
AU  - T. Y.-T. Hsu
AU  - C. Torres-Arancivia
AU  - K. Haratani
AU  - E. Ivanova
AU  - C. Paweletz
AU  - S. Cherry
AU  - D. Barbie
PY  - 2026
DA  - 2026/10/14
PB  - bioRxiv
DO  - 10.64898/2026.10.14.759171
UR  - https://www.biorxiv.org/content/10.64898/2026.10.14.759171v1
AB  - 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.
ER  -

Abstract

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