News Releases & Research Results Mechanism of action of a molecule that suppresses intracellular stress response - Drug candidate molecule for suppressing structural changes of a translation initiation factor into an inhibitory form -

The results of the international collaborative research project conducted by Team Leader Takuhiro Ito and Researcher Kazuhiro Kashiwagi of the Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research and the Cambridge Institute for Medical Research.

• The mechanism by which a molecule called ISRIB (Integrated Stress Response Inhibitor) suppresses intracellular stress response was elucidated.
• Specifically, the molecular mechanism of action of ISRIB was analyzed, demonstrating that ISRIB binds to the active structure of translation initiation factor "elF2B" to prevent structural changes of elF2B due to “phosphorylated elF2,” i.e., the inhibitor of elF2B produced in a stress environment, into an inhibitory form, thereby suppressing the progression of the ISR (integrated stress response) pathway.
• The results of this research project should facilitate the development of new therapeutic agents for neurodegenerative diseases based on the mechanism of action of ISRIB.

This project was conducted with the support of the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) by AMED.

The results were published in the scientific journal Molecular Cell on November 21.

Alisa F. Zyryanova, et al. ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B Molecular Cell
DOI: 10.1016/j.molcel.2020.10.031