Binding of the Immunosuppressant Peptide Cyclosporine A to Calcium, Zinc and Copper. Is Cyclosporine A an Ionophore?

Abstract

Cyclosporin A is an immunosuppressant drug that has made organ transplantation possible during the past decade. This conformationally flexible peptide, which interferes in an unknown way with calcium-dependent intracellular signalling events, has now been examined in aqueous and acetone solutions containing metal ions. By using electrospray mass spectrometry and nuclear magnetic resonance spectroscopy, cyclosporin A was found to bind directly to endogenous metal ions Ca²⁺, Zn²⁺ and Cu²⁺, with the highest affinity being for Ca²⁺. These observations raise the possibility that cyclosporins might directly regulate local concentrations of metal ions associated with intracellular signal transduction. This may be an important clue to the mechanism of immunoregulation by this and structurally related drugs.