Screening assay for the identification of deoxyhypusine synthase inhibitors

Abstract

The 1st step in the posttranslational hypusine [Nε-(4- amino-2-hydroxybutyl)lysine] modification of eukaryotic translation initiation factor 5A (eIF5A) is catalyzed by deoxyhypusine synthase (DHS). The eIF5A intermediate is subsequently hydroxylated by deoxyhypusine hydroxylase (DHH), thereby converting the eIF5 A precursor into a biologically active protein. Depletion of eIF5 A causes inhibition of cell growth, and the identification of eIF5 A as a cofactor of the HIV Rev protein turns this host protein and therefore DHS into an interesting target for drugs against abnormal cell growth and/or HIV replication. The authors developed a 96-well format DHS assay applicable for the screening of DHS inhibitors. Using this assay, they demonstrate DHS inhibition by AXD455 (Semapimod, CNI-1493). This assay represents a powerful tool for the identification of new DHS inhibitors with potency against cancer and HIV. © 2004 The Society for Biomolecular Screening.