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

Figure 1.

CsA chemical structure: CsA residues are: MeBmt; Abu; Sar, sarcosine; MeLeu, N‐methyl leucine; Val, valine; Ala, alanine; D‐Ala, D‐alanine; MeVal, N‐methyl valine.

Figure 2.

Conformations of CsAs in the unbound form (a) (Loosli et al., ) and in complex with Cyp18 (b) (Huai et al., ). The peptide bond between MeLeu‐9 and MeLeu‐10 in cis or trans conformations are coloured yellow. The β‐II′ turn in the unbound CsA form is coloured cyan. Hydrogen bonds are indicated as dashes.

Reproduced from Huai et al. .
Figure 3.

Molecular basis of CsA immunosuppressive activity. T‐cell activation and cytokine transcription is suppressed by inhibition of CaN catalysed NFAT dephosphorylation by binding of CsA/CypA complex to CaN.

Reproduced from Liu et al. .
Figure 4.

Ribbon representation of CyPA–CsA–CaN ternary complex (Huai et al., ). Colour codes are CaNA, red; CaNB, orange; CsA, green; CypA, blue. The ternary complex is visualised using software PyMOL Molecular Graphics System, Version 1.3.

Reproduced from Huai et al. .
Figure 5.

Structures of NIM‐811, Debio‐025 (Alisporivir) and SCY‐635. Structural elements that are added to the core CsA structure are in bold red. Structural elements that are present in CsA but not in the corresponding analogues are presented in grey colour.



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Further Reading

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Schiene‐Fischer C, Aumuller T and Fischer G (2013) Peptide bond cis/trans isomerases: a biocatalysis perspective of conformational dynamics in proteins. Topics in Current Chemistry 328: 35–67.

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Fischer, Gunter, and Malešević, Miroslav(Sep 2013) Cyclosporin. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024215]