Immunophilin

Cytokines and Immunophilins. A large number of inflammatory mediators and related proteins including the cytokines, colony stimulating factors (CSFs), interferons (IFNs), tumor necrosis factors (TNFs), growth factors (see Growth regulators), neurotrophic factors, and immunophilins are found in the mammalian CNS and appear to play a significant role in CNS function both in development and in aspects of brain homeostasis (40—43). 

Activation of immunophilin receptors in the CNS is thought to be involved in certain aspects of AIDS dementia and the CNS side effects seen with the immunosupressants, FK 506 and cyclophilin. FK 506 and related compounds also have antiischemic effects. 

FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... 

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. 

Inhibitor 1, inhibitor 2 DARPP-32, NIPP1 Inhibitor 12A, inhibitor 22A Immunophilins Cyclosporin A-cyclophilin, FK06-FK506-binding protein... 

Carver, L. and Bradfield, C., Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo, J. Biol. Chem., 272, 11452, 1997. 

Immunophilin is the generic term for a binding protein for an immunosuppressive agent, and all currently known immunophilins belong to the cyclophilin or FKBP families. The two families of immunophilins— like the small molecules they bind—don t have any readily apparent relationship. FKBP12 and CyPA have no sequence similarity, CsA does not inhibit FKBP12, and FK506 does not inhibit CyPA. 

With another immunophilin, FK binding protein (FKBP), experiments were performed using isotope editing of the [U-13C]-labeled inhibitor ascomycin (bound to unlabeled FKBP) [34], as well as by isotope filtering with unlabeled ascomycin derivatives (bound to labeled FKBP) [35],... 

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. 

Another drug whose immunosuppressive action is mediated by the complexation with a cellular protein of the immunophilins is FK506. FK506 binds to proteins of the FKBP family. The complex formed is involved in the inhibition of the phosphatase calcineurin, similar to the mode of action of CsA after binding to cyclophilin. The ACE method was used to detect... 

C. Dugave, Study of the cis-trans isomerization of the amino-acyl prolyl peptide bond. Application to the design of novel inhibitors of immunophilins, Curr. Org. Chem. 6 (2002) 1397-1431. 

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. 

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). 

Binds to an immunophilin protein to form a complex which inhibits the activation ot the mammalian Target of Rapamycin (mTOR)ulatory kinase. This inhibits T lymphocyte activation and proliferation by IL-2. IL-4, and IL-5. 

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