Jan Kühling

A Cyclosporin Derivative Discriminates between Extracellular and Intracellular Cyclophilins

One of the challenges in the pharmacological down-regulation of enzyme activity is to assure selectivity in terms of the molecular nature and intraorganismic localization of the inhibitor target. Cyclosporin A (CsA) exemplifies a rather promiscuous tight-binding inhibitor of the cyclophilin(Cyp)-like peptidyl prolyl cis/trans isomerases (PPIases, EC 5.2.1.8) that is unable to distinguish between extracellular and intracellular Cyp, nor between the various human isoforms. In addition, physiological functions of CsA have been noted that are consistent with at least two separate modes of action: 1) blocking catalyzed conformational interconversions of prolyl bonds in substrate proteins, and 2) inhibiting the protein phosphatase calcineurin (CaN) when present as a CypA/CsA binary complex.[1, 2] The latter pathway is thought to be the mechanism mediating the therapeutic effects of CsA in transplantation medicine and autoimmune diseases.[3] When applied to biological materials CsA undergoes rapid cellular uptake at 37°C,[4, 5] preferably accumulating as intracellular cyclophilin/CsA complexes.[6] Cyclophilin A (CypA) is a particularly abundant PPIase (0.19 µm in human whole blood[7]) and is thought to be the major intracellular binder of CsA.