INTERACTION OF CYCLOSPORINE-A AND 2 CYCLOSPORINE ANALOGS WITH CYCLOPHILIN - RELATIONSHIP BETWEEN STRUCTURE AND BINDING

The immunosuppressant drug cyclosporin A exists as various conformers in water. Up to 1 h is needed to reach maximum complex formation after mixing the drug with its receptor, cyclophilin, or an antibody, indic ating that only a fraction of the conformers in aqueous solution adopt s a conformation suitable for binding. In the present study we compare the binding behavior of cyclosporin to that of two analogs, using a b iosensor instrument (BIAcore, Pharmacia). The amount of complex format ion was measured as a function of time after adding the peptides to cy clophilin. The equilibrium affinity constants of cyclophilin for these analogs have been measured. The slow binding of cyclosporin to cyclop hilin compared to the instant binding of the cyclosporin analogs suppo rts the hypothesis that cyclophilin recognizes a well defined conforma tion of cyclosporin that exists in water prior to binding.