Rapamycin structurally similar

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. 

Curiously, the immunosuppressive activity of rapamycin (RAPA) does not involve the inhibition of IL-2 synthesis even though RAPA shares some structural similarities with FK506. The hF KB PI 2 RAPA complex interacts with a protein (RAFT in rat brain and FRAP in human) which controls the mRNA translation promoting the IL-2-stimulated Ga to S phase transition in T cells [6]. 

The crystal structure of the cyclophilin-CsA-calcineurin ternary structure has yet to be resolved but the ternary structure formed by rapamycin-mediated interactions between FKBP12 and the 12-kDa fKBP-rapamycin binding (FRB) domain of the 289-kDa FRAP protein has been determined with 2.7 A resolution (Choi et al, 1996), which has more recently been refined to 2.2 A resolution (Liang et al, 1999). The structure of this complex is shown in Fig. 6 (see color insert). Several similarities as well as differences in the overall mode of interaction can be seen relative to what is observed with the FKBP-FK506-cal-cineurin structure. As was seen with the FKBP-FK506 calcineurin ternary complex, there are no overall gross conformational changes... 

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. 

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 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... 

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.

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