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Structure and Binding to the Immunophilins

Ciclosporin is a hydrophobic cyclic undecapeptide (Fig. 3). In contrast, tacrolimus is a macrolide which has structural similarities to sirolimus (ra-pamycin) and everolimus but no features in common with ciclosporin. The structural dissimilarity of tacrolimus to ciclosporin and its structural connection with another immunosuppressive agent that has a different mechanism of action, sirolimus, was important in the search for the molecular targets of these agents.

Both ciclosporin and tacrolimus bind to intracellular proteins now known as immunophilins. These are ubiquitous and abundant small intracellular proteins which have been highly conserved during phylogeny (Wiederrecht, Lam et al. 1993). The major receptor for tacrolimus (FK506) is a 12-kDa protein designated FK binding protein 12 (FKBP12). The major receptor for ciclosporin is a 17-kDa protein designated cyclophilin-A (Handschumacher, Harding et al. 1984; Siekierka, Hung et al. 1989).

Despite their different structure, the immunophilins share an enzymatic activity catalysing the isomerisation of peptidyl-proline bonds; they are believed to play a role in protein folding (rotamase activity). Ciclosporin and tacrolimus are inhibitors of their cognate immunophilin's enzymatic activity, but they do not cross-inhibit the other family of immunophilins. The initial hypothesis that inhibition of the immunophilins isomerase activity played a key role in the action of these drugs was refuted by the discovery of congeners which inhibited that activity but that either differed in their mechanism of immunosuppression (sirolimus) or that lacked immunosuppressive activity altogether (Bierer et al. 1990; Dumont et al. 1990). Im-munophilins play a role in the clinical pharmacokinetics of these drugs.

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