Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants

作者：Van de Vijver Pieter; Ostrowski Tomasz; Sproat Brian; Goebels Jozef; Rutgeerts Omer; Van Aerschot Arthur; Waer Mark; Herdewijn Piet^*

来源：Journal of Medicinal Chemistry, 2008, 51(10): 3020-3029.

DOI：10.1021/jm8000746

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.

• 出版日期2008-5-22
• 单位河北医科大学