Cyclosporin immunosuppressive activity

Miller an d Rich assumed th at cyclosporin A an d its MeHrn t an alogs share a common hioactive con formation. fheir molecular mech an ics calculation s found such a conformation, fh e Boltzmann population of th e proposed hioactive conformation correlates with the immunosuppressive activities of the compounds. 

Figure 8.4b). Some of the early antihistamines were found to exert antidepressant and antipsychotic properties. These led to modem psychopharmaceuticals. The immunosuppressant activity of the fungal agent cyclosporine also was exploited for therapeutic utility. 

Cyclosporine demonstrates immunosuppressive activity by inhibiting the first phase of T-cell activation. It also inhibits release of inflammatory mediators from mast cells, basophils, and polymorphonuclear cells. It is used in the treatment of both cutaneous and arthritis manifestations of severe psoriasis. The usual dose is between 2.5 and 5 mg/kg/day given in two divided doses. Adverse effects include nephrotoxicity, hypertension, hypomagnesemia, hyperkalemia, alterations in liver function tests, elevations of serum lipids, GI intolerance, paresthesias, hypertrichosis, and gingival hyperplasia. Cumulative treatment for more than 2 years may increase the risk of malignancy, including skin cancers and lymphoproliferative disorders. 

FK-506 was isolated105 from Streptomyces trukubaensis, possessing a unique 21-membered macrolide, in particular an unusual a,/ -diketoamide hemiketo system. It shows immunosuppressive activity superior to that of cyclosporin in the inhibition of delayed hypersensitivity response in a variety of allograft transplantation and autoimmunity models. 

Cyclosporins, Fungal Metabolites with Immunosuppressive Activities... 

Table 1.4. IMMUNOSUPPRESSIVE ACTIVITY OF CYCLOSPORINS nat = natural dbs = by directed biosynthesis ps = by partial synthesis syn = by total synthesis + + +, strong immunosuppressive activity + +, moderate activity +, weak activity (+) or -, no significant activity.

In summary, it can be concluded that the main traits of the overall shape of cyclosporin A are preserved in all congeners displaying high immunosuppressive activity. Significant deviations in the backbone conformation or in the space filling and spatial arrangement of the side-chains induce a decrease in activity to a greater or lesser extent. 

All identified metabolites of cyclosporin A display only low immunosuppressive activities and do not contribute to the clinical effect of cyclosporin A. 

K. Takada, H. Yoshimura, H. Yoshikawa, S. Muranishi, T. Yasumura, and S. Oka, Enhanced selective lymphatic delivery of cyclosporin A by solubilisers and intensified immunosuppressive activity against mice skin allograft, Pharm. Res. 3 48-51 (1986). 

A Lawen, R Traber, D. Geyl. In vitro biosynthesis of [Thr2, Leu5, D-Hiv8, Leu10]-cyclosporin, a cyclosporin-related peptolide, with immunosuppressive activities by a multienzyme polypeptide. J Biol Chem 266 15567-15570, 1991. 

Ruegger, A., Kuhn, M., Lichti, H., Loosli, H., Huguenin, R. et al. (1976). Cyclosporin-A, a peptide metabolite from Trichoderma polysporum rifai, with a remarkable immunosuppressive activity. Helv. Chim. Acta 59, 1075-1092. 

Cyclosporin was isolated from the fungus Tolypocladium infiatum. Its immunosuppressive activity was discovered in 1976 [4]. Although since then many analogs have been prepared and investigated, cyclosporin A (CsA, Sandimmune, 17) remains the most effective cyclic peptide and is the major immunosuppressant dmg to prevent graft rejection after transplant surgery. 

Von Wartburg, A., Traber, R. Cyclosporins, fungal metabolites with immunosuppressive activities. Progr. Med. Chem. 1988, 25, 1-33. 

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