Infrared spectra of the cyclic peptide cyclosporin A and three analogues have been measured in a number of organic solvents (CCl4, CDCl3, acetonitrile, DMSO, and 50:50 acetonitrile:D2O). Seven of the eleven amide groups of cyclosporin A are methylated, the remaining four N-H protons forming strong intramolecular hydrogen bonds in the crystal and in CDCl3 solution. These hydrogen bonds give rise to amide I (C=O stretching) bands at positions characteristic of β-turns, γ-turns, and β-sheet domains in proteins and model polypeptides. Increasing the polarity of the solvent eliminates some of these features; however, the spectra in DMSO and acetonitrile–D2O retain strong amide I absorptions characteristic of hydrogen-bonded carbonyl groups. The conformation of cyclosporin A in water cannot be observed directly due to low solubility; these findings suggest that the structure likely retains strong intramolecular hydrogen bonding. Spectra of the three analogues are consistent with this interpretation. Implications respecting the mechanism of pharmacological action of cyclosporin A are discussed.
