Novel Backbone Conformation of Cyclosporin A: The Complex with Lithium Chloride

The complexation of cyclosporin A (CsA) with lithium chloride (LiCl) in THF-d₈ has been examined by NMR at different concentrations of LiCl. With 3 equiv of LiCl both forms of CsA, complexed and uncomplexed, are visible while at higher concentrations of lithium chloride only one conformation is observed. Two-dimensional NMR methods were used to assign the ¹Hand ¹³C NMR spectra of cyclosporin A in THF-d₈ with and without addition of excess LiCl (30.9 equiv). For the lithium-complexed CsA (Li·CsA) NOE buildup rates were measured at five mixing times at 600 MHz. The conformation has been determined by restrained molecular dynamics calculations in vacuo and an iterative relaxation matrix approach to take spin-diffusion effects into account. The lithium-complexed CsA adopts a conformation completely different from the uncomplexed CsA in THF-d₈. The latter is almost identical to the known conformation of CsA in CDCl₃. The configuration of the peptide bond between MeLeu⁹ and MeLeu¹⁰ in the lithium complex has changed from cis to trans and all transannular hydrogen bonds are disrupted in the complex, similar in this regard to the recently published conformation of CsA bound to its natural receptor cyclophilin (CyP) even though differences in the backbone conformation exist. The conformations of CsA in CDCl₃, complexed to LiCl in THF, and bound to the receptor (CsA·CyP) in H₂O are compared and discussed in light of the biological activity of this important drug.