Conformational Flexibility of Cyclosporins

Abstract

This review summarizes the present knowledge of conformations of cyclosporins mainly in the solid state. A very small chemical change of the cyclosporin backbone causes a significant change in biological properties. The mechanism of immunosuppressive activity of cyclosporin A is explained on the basis of conformational flexibility of the cyclosporin skeleton. Cyclosporin A adopts three main conformations: the tightly folded one of free cyclosporin in crystals and solution, the open one in the receptor-bound state in cyclosporin complexes with cyclophilin A and the very open one in the cyclosporin-FAB (fragment of antibody) complex. A conformational comparison of variously solvated cyclosporin A with its non-immunosuppressive derivatives (cyclosporins E and H) shows some small differences in the system of intramolecular H-bonds of cyclosporin skeletons. The inclusion effect of packed cyclosporin molecules in crystalline cyclosporin clathrates enables preferential crystallization of cyclosporins with various chiral molecules of organic solvents.