Sanglifehrin A, a Novel Cyclophilin-Binding Compound Showing Immunosuppressive Activity with a New Mechanism of Action

Abstract

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 immunosuppressant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with a new, yet undefined mechanism of action.

Inhibition of Cell Cycle Progression by the Novel Cyclophilin Ligand Sanglifehrin A Is Mediated through the NFκB-dependent Activation of p53

“…Similar to CsA, SFA binds to cyclophilin with high affinity. Unlike CsA, however, the cyclophilin-SFA complex has no effect on the phosphatase activity of calcineurin (21). Although SFA was shown to inhibit mouse and human mixed lymphocyte reactions (19), we and others have recently found that SFA does not affect T cell receptor-mediated signal transduction pathways leading to the production of cytokines such as IL-2 (21,22).…”

Cutting Edge: Sanglifehrin A, a Novel Cyclophilin-Binding Immunosuppressant Blocks Bioactive IL-12 Production by Human Dendritic Cells

“…Studies of the immunosuppressive effects of SFA have been focused on T and B lymphocytes (5,6). Thus, SFA inhibits IL-2-induced T cell proliferation and mitogen-induced B cell proliferation (5,6). Similar to Rapa, SFA has been shown to inhibit cell cycle progression of T cells at the G 1 phase (7).…”

“…SFA has been reported to exhibit lower immunosuppressive activity in the MLR when compared with CsA (1,5). Studies of the immunosuppressive effects of SFA have been focused on T and B lymphocytes (5,6). Thus, SFA inhibits IL-2-induced T cell proliferation and mitogen-induced B cell proliferation (5,6).…”

“…Although Sanglifehrin A (SFA), like CsA, binds with high affinity to cyclophilin, unlike the latter, SFA does not inhibit calcineurin phosphatase activity (5). SFA has been reported to exhibit lower immunosuppressive activity in the MLR when compared with CsA (1,5). Studies of the immunosuppressive effects of SFA have been focused on T and B lymphocytes (5,6).…”

“…The immunophilin-binding agent cyclosporin A (CsA) 3 binds to cyclophilin and inhibits activity of the calcineurin phosphatase, whereas both FK506 and rapamycin (Rapa) bind to the FK506 binding protein but inhibit two different effector proteins: calcineurin phosphatase and mammalian target of Rapa (mTOR), respectively (3,4). Although Sanglifehrin A (SFA), like CsA, binds with high affinity to cyclophilin, unlike the latter, SFA does not inhibit calcineurin phosphatase activity (5). SFA has been reported to exhibit lower immunosuppressive activity in the MLR when compared with CsA (1,5).…”