2025-07-14 カリフォルニア大学サンタバーバラ校(UCSB)
<関連情報>
- https://news.ucsb.edu/2025/021955/optogenetic-platform-illuminates-new-antiviral-strategies
- https://www.cell.com/cell/abstract/S0092-8674(25)00690-7
- https://medibio.tiisys.com/113656/
オプトジェネティクスが可能にする統合的ストレス応答モジュレーターの発見 Optogenetics-enabled discovery of integrated stress response modulators
Felix Wong ∙ Alicia Li ∙ Satotaka Omori ∙ … ∙ Hahn Kim ∙ James J. Collins ∙ Maxwell Z. Wilson
Cell Published:July 11, 2025
DOI:https://doi.org/10.1016/j.cell.2025.06.024
Graphical abstract
Highlights
- An optogenetics platform specifically induces the integrated stress response
- This platform enables a high-throughput screen of 370,830 compounds
- Identified compounds selectively eliminate ISR-high cells across diverse stressors
- These compounds demonstrate broad-spectrum antiviral activity in vitro and in mice
Summary
The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells. Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity. Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds. We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target. Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential.
