Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer

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 ISRIB’s cognitive benefits. Our results provide a framework for dissecting the ISR’s contributions within complex cellular networks, such as those governing brain function, with precise temporal and spatial resolution. Competing Interest Statement PW is an inventor on U.S. Patent 9708247 held by the Regents of the University of California that describes ISRIB and its analogs. Rights to the invention have been licensed by the University of California San Francisco to Calico Life Sciences LLC. All authors affiliated with Altos Labs are option holders or shareholders in Altos Labs, Inc. and declare no other competing interests. The remaining authors declare no competing interests.