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

We report here on the characterization of the novel immunosuppressant Sangl ifehrin 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 affi nity with the CsA binding side of CypA and inhibits its peptidyl-prolyl iso merase activity. The mode of action of SFA is different from known immunosu ppressive drugs. It has no effect on the phosphatase activity of calcineuri n, the target of the immunosuppressants CsA and FK506 when complexed to the ir binding proteins CypA and FK binding protein, respectively. Moreover, it s effects are independent of binding of cyclophilin. SFA inhibits alloantig en-stimulated T cell proliferation but acts at a later stage than CsA and F K506. In contrast to these drugs, SFA does not affect IL-2 transcription or secretion. However, it blocks IL-2-dependent proliferation and cytokine pr oduction 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 d ifferent from that of other known late-acting immunosuppressants, e.g., myc ophenolate mofetil or brequinar, as it does not affect de novo purine and p yrimidine biosynthesis. In summary, we have identified a novel inummosuppre ssant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with anew, yet undefined mechanis m of action.