Macrolides immunosuppressive activity

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. 

Pharmacology Tacrolimus is a macrolide immunosuppressant that prolongs the survival of the host and transplanted graft and inhibits T-lymphocyte activation, although the exact mechanism of action is not known. 

Pharmacology Sirolimus, a macrolide immunosuppressive agent, inhibits both T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (interleukin-2, -4, and -15) stimulation and also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK binding protein-12 (FKBP-12), to generate an immunosuppressive complex. 

Pharmacology Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. The mechanism of action of tacrolimus in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. Pharmacokinetics ... 

TAC is a macrolide antibiotic with immunosuppressive activity via inhibition of calcineurin. It was thought originally that TAC may decrease the risk of chronic allograft rejection, but experience has demonstrated that this is not the case. However, it should be noted that up to this point, TAC traditionally has been used in high-risk patients. Today, TAC is used more commonly than CSA by most transplant centers in all transplant patients, regardless of risk category. 

Many macrolides have interesting biological activities such as antiviral, antibacterial, antifungal, anthelmintic, phytotoxic, insecticidal, antitumor, and immunosuppressive activities. Those activities are due to their various biochemical activities and thus some macrolides are important tools as biochemical reagents. 

Rapamycin (sirolimus 2), isolated from Streptomyces hygroscopicus, is a highly functionalized 31-membered macrolide that exhibits potent antibiotic, cytotoxic, and immunosuppressive activity. FK506 (1) and rapamycin (2) are the structurally related macrolides (Fig. 1) thus, rapamycin possesses an a,p-diketoamide hemi-ketal system, a pipecolic acid moiety, 1,2,4-trisubstituted cyclohexane, and trisub-stituted tetrahydropyran rings, which are similar to those of FK506. In addition to these units, rapamycin (2) includes an ( , , )-triene moiety, two stereochemically complex aldol units, and 15 chiral centers beyond those found in FK506. 

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... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Tacrolimus (previously known as FK506) is a macrolide antibiotic which is obtained from the fungus Streptomyces tsukubaensis. Tacrolimus binds in-tracellularly to the protein FKBP (FK binding protein) which is distinct from the protein that binds cyclosporine. However both drug-protein complexes associate in a similar way with calcineurin and inhibits its serine/threonine phosphatase activity, although the immunosuppressive potency of tacrolimus is approximately 100 fold higher than that of cyclosporine. 

Although it is not chemically related to cyclosporine, tacrolimus (6.7) has a similar mechanism of action. Tacrolimus is an immunosuppressant macrolide antibiotic derived from Streptomyces tsukubaenis. Like cyclosporine, tacrolimus inhibits the same cytoplasmic phosphatase, calcineurin, which catalyzes the activation of a T-cell-specific transcription factor (NF-AT) involved in the biosyntheses of interleukins such as IL-2. Sirolimus (6.8) is a natural product produced by Streptomyces hydroscopicus, it blocks the ability of T cells to respond to cytokines. 

It is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. Like cyclosporine, tacrolimus binds to a cytoplasmic immunophylin and the complex inhibits the activity of the calcium dependent phosphatase known as calcineurin. This in turn, inhibits the translocation of the transcription factor NF-AT into the cell nucleus, blocking the initiation of NF-AT dependent T-cell responses. It is indicated in atopic dermatitis. 

Tacrolimus (previously known as FK506) is a macrolide antibiotic with immunosuppressive properties very similar to cyclosporin. It is more potent than cyclosporin but the side effects are similar. Tacrolimus is a very active immunosuppressive drug both in the prevention and treatment of liver and renal allograft rejection. It is especially valuable for small bowel transplantation. 

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. 

Many macrolides of marine origin have been reported to show other interesting biological properties, such as immunosuppressive [473,474], antifungal [323,475,476], anti-actin [477], and anti-inflammatory activity... 

Due to its structural complexity and interesting physiological activities as an antifungal agent and especially as an immunosuppressive drug, the macrolide rapamycin has been a target of many total syntheses [54-58]. In their approach, Ley and co-workers used a lipase-catalyzed desymmetrization of a meso diol (Fig. 3). In early studies, the selective acetylation of 7W w-2.4-dimethylpentane-1,5-diol was achieved by a PPL immobilized on celite with moderate yields and 92%... 

Sirolimus (Rapamycin, Rapamune ), a natural macrocyclic lactone, is a potent immunosuppressive agent. It was developed by Wyeth-Ayerst Laboratories (Philadelphia, Pennsylvania, U.S.A.) and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 (28,29). Sirolimus has its roots in Easter Island, where an actinomycete streptomyces hygroscopicus was found that produced a novel macrolide antibiotic with potent antibiotic, potent antifungal, immunosuppressive, and antimitotic activities. 

Sirolimus (rapamycin) is another macrolide, produced by Streptomyces hydroscopi-cus. Its immunosuppressant action, evidently, does not appear to involve inhibition of calcineurin. It forms a complex with the FK protein, imparting a special conformation on it and the complex then inhibits the mTOR (mammalian target of rapamycin) phosphatase. The latter operates in the signaling path leading from the interleukin-2 receptor to activation of mitosis in lymphocytes. Thus, sirolimus inhibits lymphocyte proliferation. It is approved for the prevention of transplant rejection. 

FK506 is the propriety name given to an immunosuppressant by a Japanese company. FK506 is a macrolide antibiotic, isolated from streptomyces tsukubaensis. It is a potent inhibitor of T cell activation, preventing allograft rejection. FK506 binds to FK-binding proteins, the FKBP s. 

Sirolimus (rapamycin) is a macrolide compound related to erythromycin and tacrolimus. It binds to the same immunophilin as tacrolimus, but it does not inhibit calcineurin. Sirolimus blocks T-cell activation at a late stage, interfering with the signal from 1L2 receptors and receptors for other cytokines and growth factors, and so blocking the cytokine or growth factor-induced activation of the proliferation cell cycle response [409]. This powerful immunosuppressive... 

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