Objective

Modulation of the integrated stress response is an emerging approach for potential therapeutic benefits in neurodegenerative diseases. The small molecule ISRIB has been shown to bind to the translation factor eIF2B, enhance its GEF activity, and thereby partially restore global protein translation which is repressed by the cellular stress response. At the same time, translation of the transcription factor ATF4, which is induced by the stress response pathway, is reduced by ISRIB.

We have found that the enhancement of translation can be detected in an in-vitro system, using commercial kit reagents derived from a human cell line. ISRIB and its steroisomer cis-ISRIB increased translation of a GFP reporter in a dose-dependent manner, with the expected rank order of potencies. Experiments were extended to additional compounds which have been published as repurposed drugs also targeting translation repression, trazodone hydrochloride and dibenzoylmethane. However, no effect of these compounds on in-vitro translation was found in our system, suggesting that a different mechanism is responsible for their activity.