Sommer Marc-Nicola, Bevec Dorian, Klebl Bert, Flicke Birgit, Hölscher Kerstin, Freudenreich Tatjana, Hauber Ilona, Hauber Joachim, Mett Helmut
Department of Assay Development and Screening, Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, D-81377 München, Germany.
J Biomol Screen. 2004 Aug;9(5):434-8. doi: 10.1177/1087057104264031.
The 1st step in the posttranslational hypusine [N(epsilon)-(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 eIF5A precursor into a biologically active protein. Depletion of eIF5A causes inhibition of cell growth, and the identification of eIF5A 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.
真核生物翻译起始因子5A（eIF5A）的翻译后羟赖氨醛[ N（ε）-（4-氨基-2-羟丁基）赖氨酸]修饰的第一步由脱氧羟赖氨醛合酶（DHS）催化。随后，eIF5A中间体被脱氧羟赖氨醛羟化酶（DHH）羟基化，从而将eIF5A前体转化为具有生物活性的蛋白质。eIF5A的缺失会导致细胞生长受到抑制，而eIF5A作为HIV Rev蛋白的辅因子被鉴定出来，这使得这种宿主蛋白以及DHS成为针对异常细胞生长和/或HIV复制的药物的一个有趣靶点。作者开发了一种适用于筛选DHS抑制剂的96孔板格式的DHS检测方法。利用该检测方法，他们证明了AXD455（司美匹莫德，CNI-1493）对DHS的抑制作用。该检测方法是鉴定对癌症和HIV有效的新型DHS抑制剂的有力工具。
