CONFORMATIONAL STUDY OF CYCLOSPORINE-A IN ACETONE AT LOW-TEMPERATURE

The conformation of cyclosporin A (CsA), an undecapeptide with seven N -methylated amino acids, was studied in acetone at 193 K. Previous stu dies of the conformation of CsA in different solvents, in the cyclospo rin-cyclophilin complex and in complexes with LiCl showed that the con formation of the free and the bound CsA are different. Differences wer e observed at the conformation of the MeLeu(9)-MeLeu(10) peptide bond, which is cis in solution and trans in the complex, and in the orienta tion of the amide protons and the N-Me groups. By using acetone, which is a proton acceptor, we wanted to influence the orientation of the a mide protons. In the conditions used in this study a new conformation is found, which differs as well from the one previously observed in so lution as from the conformation observed in the complex. This conforma tion has a cis peptide bond between MeLeu9 and MeLeu10 The trans confo rmation of the peptide bond MeLeu(9)-MeLeu(10), which is necessary for biological activity, was not induced. One of the amide protons is inv olved in an intramolecular H-bridge stabilising a beta-turn around Sar (3)MeLeu(4), and three of the seven NMe groups are oriented to the cen tre of the molecule. (C) Munksgaard 1994.