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Cyclosporin

  1. Gunter Fischer1,
  2. Miroslav Malešević2

Published Online: 20 SEP 2013

DOI: 10.1002/9780470015902.a0024215

eLS

eLS

How to Cite

Fischer, G. and Malešević, M. 2013. Cyclosporin. eLS. .

Author Information

  1. 1

    Max-Planck Institute for Biophysical Chemistry, Göttingen, Halle (Saale), Germany

  2. 2

    Martin-Luther-University Halle-Wittenberg Halle, Weinbergweg, Halle (Saale), Germany

Publication History

  1. Published Online: 20 SEP 2013

Abstract

Abstract

The cyclosporin family of secondary metabolites isolated from the fungus Tolypocladium inflatum is characterised by a cyclopeptide structure consisting of an 11-membered amino acid ring, containing N-methylated peptide bonds. Parent cyclosporin A (CsA) is a drug widely used to prevent and treat rejection episodes after organ transplantation and can be used in autoimmune diseases. It is immunosuppressive, anti-inflammatory, antichemotactic and antiviral but CsA-induced immunosuppression and nephrotoxicity cause limitations in its general use in clinical practice. In lymphoid cells, after binding to its receptor cyclophilin A (CypA), CsA acts via gain-of-function inhibiting the protein phosphatase calcineurin and thus the transcription of several cytokines. Nonimmunosuppressive CsA derivatives lacking gain-of-function in the cell result from semisynthetic procedures mostly modifying its MeLeu-4 side chain. These derivatives strongly inhibit the prolyl cis/trans isomerase activity of CypA, which, in turn, is a host cell factor for viral infections and other pathophysiological states in human diseases.

Key Concepts:

  • Beside its use in transplantation medicine, treatment of other human disorders with CsA has some limitations due to immunosuppression and toxicity.

  • Immunosuppressive activity can be successfully removed from the cyclosporine molecule using a variety of Leu-4 substituted CsA derivatives.

  • Nonimmunosuppressive CsA derivatives can retain the high potency of CsA in inhibiting the prolyl cis/trans isomerase activity of the CsA receptor CypA.

  • Nonimmunsuppressive CsA derivatives have been utilised to launch clinical phase studies for the treatment of hepatitis C virus infections.

  • A broad antiviral activity of nonimmunosuppressive CsA derivatives in addition to the anti-HCV profile has been suggested.

  • CsA derivatives have been designed to target cyclophilins in specific tissues and organelles.

  • Extracellularly restricted CsA derivatives are potent drug candidates to combat chronic inflammations.

Keywords:

  • immunosuppression;
  • inhibition;
  • cyclophilin;
  • calcineurin;
  • viral infection;
  • inflammation