Immunosuppressive action rapamycin

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

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. 

The molecular targets of rapamycin inhibitors (mTOR), siroiimus and everoiimus, have a distinct mechanism of immunosuppressive action different from the calcineurin inhibitors cyclosporine and TAC. As such, they are expected to be minimally nephrotoxic per se. 

FRAP inhibits its function in T lymphocytes, which results in impaired interleukin-2 receptor signaling [31-34], and this is thought to be the basis for the immunosuppressive actions of rapamycin [30]. Another example of an immunosuppressant that acts in this manner is cyclosporin A, which interacts with cyclophilin to form a complex that then binds calcineurin [30]. 

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

Sehgal SN. 2006. Rapamune (RAPA, rapamycin, sirolimus) mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 39 484-489. 

Mechanism of Action. Unlike other immunosuppressants (cyclosporine, tacrolimus), sirolimus does not interfere directly with cytokine production. Instead, sirolimus inhibits the function of a specific enzyme commonly known as the mammalian target of rapamycin (mTOR).37,42 This enzyme plays a key role in signaling pathways that promote the growth and proliferation of T and B cells.37,45 By inhibiting this enzyme, sirolimus causes cell division to stop at a specific stage (Gl), thereby limiting the ability of these cells to mount an attack on transplanted tissues.65... 

Studies on the exact mode of action of the unmodified sanglifehrin A (1) by Liu et al. found that 1 inhibits the T cell cycle (G1 phase), mediated by activation of the tumor suppressor gene p53 [21]. Sanglifehrin A (1) is a novel immunosuppressant, which, in addition to CsA, FK506, and rapamycin, represents a fourth class of immunophilin-binding metabolites with a new, as yet undefined mechanism of action [22]. The structural variation now accessible through total and partial synthesis should contribute to understanding of its bio-... 

The structurally related compounds rapamycin 71, FK506 72 and FK520 73 demonstrate antitumour, antifungal and immunosuppressant activities. This latter immunosuppressant activity has generated great interest due to applications in the therapeutic area of organ transplant surgery, and a detailed model for their mode of action has been developed [103]. Due to the similarity of their structures and the parallel biosynthetic studies, rapamycin will be the focus of this section and cross reference will be made where appropriate. 

Sirohmus (SRL), also known as rapamycin, is another immunosuppressive macrolide antibiotic that is structurally similar to TAG. It represents the first in the newest class of immunosuppressants, with a unique mechanism of action. The potential of SRL to decrease the incidence of chronic rejection remains to be seen. 

This section covers compounds that were reported relatively recently. The mechanism of action of these compounds is reasonably understood. The compounds in this section have been sorted by their biological activity and their potential utility in the clinic. The class of compounds include immunosuppressants (rapamycin and FK506), antitumor agents (geldanamycin to echinomycin), antiinflammatory agents (efomycin), antiobesity agents (lipstatin), and antibiotics (streptogramins to platensimycin). 

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). ... 

Based on the different mechanism of action from cyclosporin and tacrolimus, rapamycin has been investigated as an adjunctive immunosuppressant agent for prevention of rejection after organ transplantation in combination with these agents. 

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