小分子筛选确定了硒氮杂环药物依布硒啉是二价金属离子转运体1介导的铁摄取的有效抑制剂。
Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake.
作者信息
Wetli Herbert A, Buckett Peter D, Wessling-Resnick Marianne
机构信息
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
出版信息
Chem Biol. 2006 Sep;13(9):965-72. doi: 10.1016/j.chembiol.2006.08.005.
HEK293T cells overexpressing divalent metal transporter-1 (DMT1) were established to screen for small-molecule inhibitors of iron uptake. Using a fluorescence-based assay, we tested 2000 known bioactive compounds to find 3 small molecules that potently block ferrous iron uptake. One of the inhibitors, ebselen, is a seleno compound used in clinical trials as a protective agent against ischemic stroke. Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 microM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake. An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 microM). Both ebselen and PDTC increased cellular levels of reduced glutathione. These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition.
建立了过表达二价金属转运蛋白1（DMT1）的人胚肾293T细胞（HEK293T），用于筛选铁摄取的小分子抑制剂。使用基于荧光的检测方法，我们测试了2000种已知的生物活性化合物，以找到3种能有效阻断亚铁摄取的小分子。其中一种抑制剂依布硒仑是一种硒化合物，在临床试验中用作抗缺血性中风的保护剂。依布硒仑抑制Fe（II）摄取（IC50约为0.22μM），但不影响Fe（III）转运或DMT1介导的锰摄取。一种无关的抗氧化剂吡咯烷二硫代氨基甲酸盐（PDTC）也抑制DMT1活性（IC50约为1.54μM）。依布硒仑和PDTC均增加了细胞内还原型谷胱甘肽的水平。这些观察结果表明，DMT1介导的Fe（II）转运可受细胞氧化还原状态的调节，并提示依布硒仑可能通过抑制转运来限制铁催化的损伤，从而发挥治疗作用。
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