Conformational Flexibility of Cyclosporins
aDepartment of Solid State Chemistry, Institute of Chemical Technology, Prague, bGalena Co., Research Unit, Ceske Budejovice
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.
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