Optogenetics-enabled discovery of integrated stress response modulators

Area of Science:

• Cellular Biology
• Pharmacology
• Optogenetics

Background:

• The integrated stress response (ISR) is crucial for cellular homeostasis.
• Modulating the ISR is therapeutically relevant for cancer, viral infections, and neurodegeneration.
• Existing compounds often exhibit toxicity, limiting their therapeutic use.

Purpose of the Study:

• To develop an optogenetic platform for high-throughput screening of compounds targeting the ISR.
• To identify novel compounds that selectively modulate the ISR without cytotoxicity.
• To explore the therapeutic potential of identified ISR modulators.

Main Methods:

• Optogenetic clustering of PKR to induce ISR-mediated cell death.
• High-throughput screening of 370,830 compounds.
• Mechanistic studies involving ATF4 and GCN2.
• In vitro and in vivo antiviral assays.

Main Results:

• Identified compounds that potentiate ISR-mediated cell death without cytotoxicity.
• Discovered that these compounds upregulate activating transcription factor 4 (ATF4).
• Identified GCN2 as a molecular target and demonstrated antiviral activity, including in a mouse model.

Conclusions:

• An optogenetic platform enables efficient drug discovery for ISR modulators.
• Novel ISR potentiators with therapeutic potential were identified.
• These compounds show promise for treating viral infections and other stress-related diseases.