Sanglifehrin A, a novel cyclophilin-binding compound showing immunosuppressive activity with a new mechanism of action

被引:94
作者
Zenke, G
Strittmatter, U
Fuchs, S
Quesniaux, VFJ
Brinkmann, V
Schuler, W
Zurini, M
Enz, A
Billich, A
Sanglier, JJ
Fehr, T
机构
[1] Novartis Pharma AG, Transplantat Res, CH-4002 Basel, Switzerland
[2] Novartis Pharma AG, Core Technol, CH-4002 Basel, Switzerland
[3] Novartis Pharma AG, Nervous Syst Res, CH-4002 Basel, Switzerland
[4] Novartis Res Inst, Vienna, Austria
关键词
D O I
10.4049/jimmunol.166.12.7165
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
We report here on the characterization of the novel immunosuppressant Sanglifehrin A (SFA). SFA is a representative of a class of macrolides produced by actinomycetes that bind to cyclophilin A (CypA), the binding protein of the fungal cyclic peptide cyclosporin A (CsA). SFA interacts with high affinity with the CsA binding side of CypA and inhibits its peptidyl-prolyl isomerase activity. The mode of action of SFA is different from known immunosuppressive drugs. It has no effect on the phosphatase activity of calcineurin, the target of the immunosuppressants CsA and FK506 when complexed to their binding proteins CypA and FK binding protein, respectively. Moreover, its effects are independent of binding of cyclophilin. SFA inhibits alloantigen-stimulated T cell proliferation but acts at a later stage than CsA and FK506. In contrast to these drugs, SFA does not affect IL-2 transcription or secretion. However, it blocks IL-2-dependent proliferation and cytokine production of T cells, in this respect resembling rapamycin. SFA inhibits the proliferation of mitogen-activated B cells, but, unlike rapamycin, it has no effect on CD154/IL-4-induced Ab synthesis. The activity of SFA is also different from that of other known late-acting immunosuppressants, e.g., mycophenolate mofetil or brequinar, as it does not affect de novo purine and pyrimidine biosynthesis. In summary, we have identified a novel inummosuppressant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with anew, yet undefined mechanism of action.
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页码:7165 / 7171
页数:7
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