STRUCTURE-BASED DESIGN OF A CYCLOPHILIN-CALCINEURIN BRIDGING LIGAND

The affinity of a flexible ligand that adopts a specific conformation when bound to its receptor should be increased with the appropriate us e of conformational restraints. By determining the structure of protei n-ligand complexes, such restraints can in principle be designed into the bound ligand in a rational way. A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferatio n of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, w as designed with the known three-dimensional structure of a cyclophili n-CsA complex. The conformational restraints in TCsA appear to be resp onsible for its greater affinity for cyclophilin and calcineurin relat ive to CsA.