Conformation of MeAla6‐cyclosporin A by NMR: Relationship of sidechain orientation of the MeBmt‐l, MeLeu‐9, and MeLeu‐10 residues to immunosuppressive activity

Abstract

MeAla6‐cyclosporin A (MeAla6‐CsA) is a unique CsA analog that shows weak immunosuppressive activity and yet binds strongly to the proposed cytosolic protein receptor, cyclophilin (CyP). Preliminary 1H NMR data showed significant chemical shift differences between spectra of MeAla6‐CsA and CsA, suggesting different preferred conformations. A more detailed study, however, revealed that the backbone conformations of the two molecules are essentially identical, and that the differences can be accounted for, principally, by the sidechain motions of the MeBmt‐1, MeLeu‐9, and ‐10 residues. ROE and coupling constant data show that in MeAla6‐CsA, the preferred χ1 rotamers for MeLeu‐9 and ‐10 are + 18..