Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants.
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 IC50 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.
Van de Vijver
Pieter
P
Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Catholic University of Leuven, Leuven, Belgium.
Ostrowski
Tomasz
T
Sproat
Brian
B
Goebels
Jozef
J
Rutgeerts
Omer
O
Van Aerschot
Arthur
A
Waer
Mark
M
Herdewijn
Piet
P
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D013329:Structure-Activity Relationship
D000596:Amino Acids; D007166:Immunosuppressive Agents; D000604:Amino Acyl-tRNA Synthetases; D000241:Adenosine