2. Academic Validation
  3. Pharmacological targeting of RIG-I can selectively activate the integrated stress response

Pharmacological targeting of RIG-I can selectively activate the integrated stress response

  • Sci Adv. 2025 Oct 31;11(44):eadt3014. doi: 10.1126/sciadv.adt3014.
Caroline A Cuoco 1,  Wen Ren 1,  Kelsey R Baron 2,  Sakina Gologo 1,  Valerie Perea 2,  Prakhyat Mathur 2 3,  Prerona Bora 2,  Amina Ta 3,  Alan Chu 4,  Rama Aldakhlallah 2,  Derek Rhoades 1,  Christian M Cole 1,  Ee Phie Tan 1,  William C Hou 1,  Leonard Yoon 1,  Xiaoyan Guo 5,  Jessica D Rosarda 2 6,  Phil S Baran 1,  Martin Kampmann 5 7,  Lakeisha Tillery 4,  Kristen A Johnson 4,  Evan T Powers 1,  R Luke Wiseman 2,  Jeffery W Kelly 1 8
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 2 Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 3 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 4 The California Institute for Biomedical Research, La Jolla, CA, USA.
  • 5 Institute for Neurodegenerative diseases, University of California, San Francisco, San Francisco, CA, USA.
  • 6 Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 7 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 8 The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
PMID: 41160678 DOI: 10.1126/sciadv.adt3014
Abstract

The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.

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