Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer

Boone, M.; Dalwadi, U.; Deal, A.; Zhu, P. J.; Croll, T. I.; Yamazaki, M.; Prescott, K.; Minopoli, R.; Biscocho, I.; Wang, J.; Lee, D. J.; Arthur, C. P.; Laughlin, T. G.; Zhou, H.; Klope, M. T.; Egea, P. F.; Schoof, M.; Lawrence, R.; Renslo, A. R.; Costa-Mattioli, M.; Frost, A.; Walter, P.

doi:10.64898/2026.02.04.700910

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bioRxiv · 10.64898/2026.02.04.700910

Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer

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Abstract

The Integrated Stress Response (ISR) couples cellular stress sensing to translational control, playing a critical role in the homeostatic regulation of cell health. However, prolonged and unmitigated ISR activation becomes maladaptive and drives the progression of a wide range of pathologies, including cognitive decline. Pharmacological inhibition of the ISR with the small, drug-like molecule ISRIB has proven remarkably effective in reversing cognitive deficits and pathology in animal models, highlighting its potential for therapeutic intervention in humans. We engineered an allele-specific ISRIB analog (mISRIB) that selectively targets a mutant form of eIF2B, the molecular target of ISRIB, without affecting wild-type eIF2B. Notably, mISRIB treatment in mice homozygous for the eIF2B mutant allele enhances synaptic plasticity and long-term memory, confirming the on-target mechanism underlying ISRIBs cognitive benefits. Our results provide a framework for dissecting the ISRs contributions within complex cellular networks, such as those governing brain function, with precise temporal and spatial resolution.

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Boone, M., Dalwadi, U., Deal, A., Zhu, P. J., Croll, T. I., Yamazaki, M., Prescott, K., Minopoli, R., Biscocho, I., Wang, J., Lee, D. J., Arthur, C. P., Laughlin, T. G., Zhou, H., Klope, M. T., Egea, P. F., Schoof, M., Lawrence, R., Renslo, A. R., Costa-Mattioli, M., Frost, A., Walter, P.. 2026-02-07. Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer. https://doi.org/10.64898/2026.02.04.700910

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