From protein folding to cognition: a serendipitous path of discovery

A screen for small molecule modulators of the unfolded protein response yielded ISRIB, a drug-like compound that with high efficacy renders cells insensitive to translational inhibition by phosphorylation of eIF2. ISRIB is an activator of eIF2B, eIF2’s guanine nucleotide exchange factor, and a cognitive enhancer in rodents, significantly improving long-term memory of wild-type animals in behavioral assays.