Elucidating the mode of action of gephyronic acid

Gephyronic acid is a cytotoxic polyketide isolated from myxobacterium Archangium gephyra. The cytotoxic effects of this compound is a result of translation inhibition¹. However, the mechanism by which gephyronic acid inhibits translation is still unclear. Translation is an essential cellular process that is controlled on a temporal and spatial manner. The four steps of translation are initiation, elongation, termination, and ribosome recycling². Of these, the most important and the rate limiting step is initiation. Our current results suggest that gephyronic acid inhibits translation by binding to eukaryotic initiation factor 2 alpha (eIF2a). Using in vitro and in vivo luciferase assays we have reiterated gephyronic acid as translation inhibitors. Using drug affinity responsive target stability (DARTS)³ the direct target of gephyronic acid was found to be eIF2a. Apart from binding, it also induces phosphorylation of eIF2a which has been shown by immunofluorescence using PtK2 cells.

In conclusion, gephyronic acid inhibits translation by binding to eIF2a. This is the first small molecule known to have eIF2a as a direct target and thereby derails translation. The binding of the compound to the protein probably alter the conformations and interferes with exchanging of GDP by GTP which is needed for its activity. This seems to be a novel mode of translation inhibition.