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Updated: May 8, 2026
10:59
Analysis of Translation Initiation During Stress Conditions by Polysome Profiling
Published on: May 19, 2014
A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response
Fiona Shilliday1, Miguel Gancedo-Rodrigo2, Ginto George3
1Discovery Sciences, R&D, AstraZeneca, Cambridge, UK. fiona.shilliday@astrazeneca.com.
Nature Communications
|May 6, 2026
Summary
Researchers discovered small molecules that stabilize inactive eIF2B, activating the Integrated Stress Response (ISR). This finding supports targeting eIF2B for therapeutic ISR activation, offering new treatment possibilities.
Area of Science:
- Molecular Biology
- Biochemistry
- Drug Discovery
Background:
- Eukaryotic initiation factor 2B (eIF2B) is a guanine nucleotide exchange factor essential for protein synthesis.
- Stress-induced phosphorylation of eIF2 triggers the Integrated Stress Response (ISR).
Purpose of the Study:
- To identify modulators of eIF2B activity.
- To explore the therapeutic potential of targeting eIF2B for ISR activation.
Main Methods:
- DNA-encoded chemical library (DEL) screening.
- Cryo-electron microscopy (Cryo-EM) to determine compound-bound eIF2B structure.
- Cell-based assays to assess compound activity.
Main Results:
- Identified a chemical series that stabilizes the inactive state of eIF2B.
- Cryo-EM revealed a conformational switch to the inactive state.
- Compound activity is dependent on eIF2 phosphorylation status and ISRIB competition.
Conclusions:
- Established the feasibility of targeting eIF2B with allosteric inhibitors.
- Demonstrated that these inhibitors act as ISR activators (ISACs).
- Paved the way for therapeutic strategies based on eIF2B-directed ISR activation.
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