2. Academic Validation
  3. Optogenetics-enabled discovery of integrated stress response modulators

Optogenetics-enabled discovery of integrated stress response modulators

  • Cell. 2025 Sep 4;188(18):4950-4967.e22. doi: 10.1016/j.cell.2025.06.024.
Felix Wong 1,  Alicia Li 2,  Satotaka Omori 2,  Ryan S Lach 2,  Jose Nunez 2,  Yunke Ren 2,  Sean P Brown 2,  Vipul Singhal 2,  Brent R Lyda 2,  Taivan Batjargal 2,  Ethan Dickson 3,  Jose Roberto Rodrigues Reyes 3,  Juan Manual Uruena Vargas 4,  Shalaka Wahane 5,  Hahn Kim 6,  James J Collins 7,  Maxwell Z Wilson 8
Affiliations

Affiliations

  • 1 Integrated Biosciences, Redwood City, CA 94065, USA. Electronic address: felix@integratedbiosciences.com.
  • 2 Integrated Biosciences, Redwood City, CA 94065, USA.
  • 3 Center for BioEngineering, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Biomolecular Science and Engineering Program, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
  • 4 NSF BioPACIFIC Materials Innovation Platform, California NanoSystems Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
  • 5 Illumina Ventures, Foster City, CA 94404, USA.
  • 6 Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
  • 7 Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: jimjc@mit.edu.
  • 8 Integrated Biosciences, Redwood City, CA 94065, USA; Center for BioEngineering, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Biomolecular Science and Engineering Program, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. Electronic address: max@integratedbiosciences.com.
PMID: 40651473 DOI: 10.1016/j.cell.2025.06.024
Abstract

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.

Keywords

antiviral; drug discovery; endoplasmic reticulum stress; integrated stress response; optogenetics; phenotypic screening; proteostasis; small molecules; synthetic biology; unfolded protein response.

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