Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants

被引：27

作者：

Van de Vijver, Pieter ^{[1
]}

Ostrowski, Tomasz

Sproat, Brian

Goebels, Jozef ^{[2
]}

Rutgeerts, Omer ^{[2
]}

Van Aerschot, Arthur ^{[1
]}

Waer, Mark ^{[2
]}

Herdewijn, Piet ^{[1
]}

机构：

[1] Katholieke Univ Leuven, Rega Inst Med Res, Med Chem Lab, B-3000 Louvain, Belgium

[2] Katholieke Univ Leuven, Lab Expt Transplantat, B-3000 Louvain, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 10期

关键词：

D O I：

10.1021/jm8000746

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5'-O-(N-L-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC(50) of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.

引用

页码：3020 / 3029

页数：10

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