A deep learning-generated hASIC1a miniprotein inhibitor confers neuroprotection in stroke
- 1University of Copenhagen
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.
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BibTeX
@misc{sormann2026deep,
title = {{A deep learning-generated hASIC1a miniprotein inhibitor confers neuroprotection in stroke}},
author = {J. Sormann and K. Epitropaki and M. F. Vicino and C. L. Fjorbak and C. F. Pugh and B. Lang and E. K. Beyer and R. Comaposada-Baro and F. Hink and S. Friis and S. G. Usher and C. Cai and H. E. Autzen and J. M. Rogers and S. Pless},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.04.755611},
url = {https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A deep learning-generated hASIC1a miniprotein inhibitor confers neuroprotection in stroke
AU - J. Sormann
AU - K. Epitropaki
AU - M. F. Vicino
AU - C. L. Fjorbak
AU - C. F. Pugh
AU - B. Lang
AU - E. K. Beyer
AU - R. Comaposada-Baro
AU - F. Hink
AU - S. Friis
AU - S. G. Usher
AU - C. Cai
AU - H. E. Autzen
AU - J. M. Rogers
AU - S. Pless
PY - 2026
DA - 2026/10/04
PB - bioRxiv
DO - 10.64898/2026.10.04.755611
UR - https://www.biorxiv.org/content/10.64898/2026.10.04.755611v1
AB - 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.
ER -