Rapamycin and cyclosporine

C. Vidal, G.l. Kirchner, G. Wilnsch, K.-F. Sewing, Automated simultaneous quantification of the immunosuppressants 40-O-(2-hydroxyethyl) rapamycin and cyclosporin in blood with ESI-MSc detection, Clin. Chem., 44 (1998) 1275. 

Figure 3. Nonimmunosuppressive immunophilin ligands used to probe the mechanism of action of FK506, rapamycin, and cyclosporin A.

Two new immunophilins have recently been discovered which contain both FKBP and cyclophilin domains. A 37 kDa protein isolated from the Jurkat T-cell line was found to bind FK506, rapamycin, and cyclosporin A, all with high affinity.50 FKBP37 contains two FKBP domains and one cyclophilin domain, and also possesses glyceraldehyde 3-phosphate dehydrogenase activity. The 52 kDa protein, isolated from human lymphoid cells, also binds all three immunosuppressant drugs but shows no detectable rotamase activity towards a variety of peptidic substrates.95... 

The results with FK506, rapamycin, and cyclosporin A discussed above indicate that immunophilin ligands possess neuroprotective and neuroregenerative properties, and that both calcineurin-dependent and calcineurin-independent mechanisms are operative. The observation that both FK506 and rapamycin produced neurotrophic effects in vitro suggested that the nerve growth effects of the drugs were mediated, at least in part, by a non-calcineurin mechanism. 

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

Attur MG, Patel R,ThakkerG,Vyas P, Levartovsky D, Patel P, Naqvi S, Raza R, Patel K, Abramson D, Bruno G, Abramson SB, Amin AR. Differential antl-Inflammatory effects of immunosuppressive drugs cyclosporin, rapamycin and FK-506on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production. Inflamm Res 2000 49 20-26. 

One of the critical features of any discussion of the mechanisms of immune suppression must be the appreciation that robust changes in immune function can be mediated by either direct or indirect effects (or both) of a xenobiotic. Direct effects can be associated with distinct types of cells. Perhaps the best examples are cyclosporin A and related immunosuppressive drugs, such as rapamycin and FK-506, which specifically target T cells via an interaction with cytosolic and/or nuclear proteins to disrupt antigen-induced activation of transcription. To date, despite the tremendous evolution of the discipline of immunotoxicology, no other xenobiotic associated... 

Medicinal and herbal extracts form the basis for the health care of approximately 80% of the world s population some 21,000 plant species are used world-wide. Screening of natural products led to the discovery of the immunosuppressants, cyclosporin, rapamycin, and FK 506 (153), and there is a continued search for new compounds, even in relatively well-explored areas such as China (154). 

FK506 (tacrolimus) (23) is a 23-membered macrocyclic lactone isolated from Streptomyces tsukubaensis and is structurally related to rapamycin. It displays antifungal and immunosuppressive activities. It is marketed as an immunosuppressant that can be used in transplant therapy and several autoimmune disorders. Rapamycin and FK506 share the same common cellular receptor FKBP, but they present a different mechanism of action. Similar to cyclosporine A, FK506 suppresses T-cell activation at the level of lymphokine production and prevents the expression of the interleukin 2 receptor (IL-2R). ... 

Rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Rapamycin has a chemical structure partially similar to that of tacrolimus (Fig. 2). It was first isolated from Streptomyces hygro-scopicus strains found in soil obtained on Rapa Nui (Easter Island), hence the name rapamycin [19, 20]. This compound was initially investigated as an antifungal agent and later found to have immunosuppressive activity [21]. Rapamycin also binds to FKBP, but its immunosuppressive mechanisms are distinct from those of tacrolimus and cyclosporin in that it does not act via the calcineurin pathway [22, 23]. The immunosuppressive effects of rapamycin result from its inhibition of T-cell [23, 24] and B-cell [25] proliferation. The key effect on those cells results from the blocking of the signals of several cytokines (IL-2 and IL-4), leading to interruption of the cell cycle from the G, to the S phase. Unlike tacrolimus, the complex of rapamycin and FKBP-12 does not inhibit the dephosphorylase... 

Fig. 1. The structure of cyclosporin A (CsA), FK506, rapamycin, and FK506 s derivatives. Note the common structural features of FK506, rapamycin, GPI-1046 and V-10,367, while CsA has an entirely different chemical stracture. Despite their structural differences, CsA and FK506, as immunosuppressants, exhibit a nearly identical spectrum of action on T lymphocytes. In contrast, regardless of their stractural similarity, FK506 and rapamycin exhibit quite different spectra of action on T lymphocytes, though both FK506 and rapamycin are powerful immunosuppressants. GPI-1046 and V-10,367 do not have any immunosuppressive activity however, they have neurotrophic activities as do FK506 and rapamycin.

Chemically, cyclosporin A is a cyclic peptide of eleven amino acid residues, very different from FK506 and rapamycin. FK506, although slightly smaller, resembles rapamycin, and their structures are partly identical. Surprisingly, it is FK506 and cyclosporin A that share almost... 

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