Therapeutic potential of cyclophilin inhibitors

The archetypical cyclophilin inhibitor drug is cyclosporin, first approved in 1983 (Sandimmune™) as an immunosuppressant to prevent organ transplant rejection. This activity was early on recognised as a selective block of early T cell activation. Years later that it was demonstrated by Schreiber and Liu1 that it was in effect the complex of cyclosporin with cyclophilin that bound to a third protein, calcineurin, forming a ternary complex in which the catalytic activity of calcineurin as a serine/threonine phosphatase is inhibited. This activity in turn is required to activate the transcription factor NFAT for IL-2 gene transcription and launch of a specific immune response.

In the ternary complex cyclosporin:cyclophilin:calcineurin it is not only the calcineurin activity that is inhibited but also that of cyclophilin. Therefore, the pharmacological activity profile of cyclosporin is composed of two different activity categories, (1) that of cyclophilin inhibition and (2) that of calcineurin inhibition. It was recognised early on during the development of cyclosporin, that certain cyclosporin analogues and derivatives had equal affinity to cyclophilin but lacked immunosuppressive activity (i.e. were more selective), demonstrating that cyclophilin inhibition could be separated from immunosuppression.

Following solid organ transplantation, the use of cyclosporin was approved for a number of other indications, including Rheumatoid Arthritis, Psoriasis, Graft vs Host Disease, Xerophthalmia, Atopic Dermatitis, Aplastic Anaemia, Myasthenia Gravis, Lupus Nephritis, others. The database ClinicalTrials.gov lists over 250 current trials with cyclosporin for indications other than transplantation or graft vs host disease. These include chronic inflammatory and autoimmune diseases, solid and blood cancers, diseases associated with ischaemia such as myocardial infarct, stroke, traumatic brain injury and others and mitochondrial diseases such as LHON.

Whilst there is a solid scientific rationale justifying all these trials, the actual practical use of cyclosporin is severely limited by several of its properties: (i) immunosuppressive activity, (ii) dose-limiting toxicity, (iii) poor PK profile, (iv) lack of an injectable form due to extreme insolubility.

The Cypralis technology overcomes these drawbacks.

Reference

  1. Liu, JO et al., “Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes”, Cell 1991 Aug 23; 66(4):807-15

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