Drugs acting on immunophilins: Cyclosporine, Tacrolimus, Sirolimus

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

(This article is based in large part on Wikipedia articles that were reviewed for accuracy, please see the reference links).

Cyclosporine A and tacrolimus were isolated from soil organisms inhibit T-helper functions. They are structurally different but a similar mechanism of action. Cyclosporine and tacrolimus are available in oral and intravenous form. Topical tacrolimus and pimecrolimus are approved for atopic dermatitis. Cyclosporine was ineffective in topical form.


Cyclosporine and FK-506 block T cell cytokine production by inhibiting activation of the NFAT transcription factor (note: different from NFkB).

Ciclosporin (INN), cyclosporine (USAN) or cyclosporin (former BAN). Image source: Wikipedia, public domain.

Together with tacrolimus, cyclosporine is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs. Initially isolated from a Norwegian soil sample, Ciclosporin A, the main form of the drug, is a cyclic peptide of 11 amino acids produced by the fungus Beauveria nivea.

The immuno-suppressive effect of cyclosporin was discovered on January 31, 1972, by employees of Sandoz (now Novartis) in Basel, Switzerland. The success of Cyclosporin A in preventing organ rejection was shown in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on March 9, 1980, was a 28-year-old woman. Cyclosporin was subsequently approved for use in 1983.

Cyclophilin. Image source: Wikipedia, public domain.

Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of lymphocytes, especially T-cells. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normally induces the transcription of interleukin-2.

Cyclosporin has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants such as tacrolimus (Prograf) (see below).


Tacrolimus is a 23-member macrolide produced by Streptomyces tsukubaensis. The name tacrolimus is derived by taking the "t" for Mount Tsukuba (where the organism was discovered), "acrol" for macrolide and "imus" for immunosuppressant. It is also referred to as FK506, its research compound designation.

Cyclosporine and FK-506 block T cell cytokine production by inhibiting activation of the NFAT transcription factor (note: different from NFkB).

Tacrolimus (FK-506 or Fujimycin, trade name Prograf) is a product of the fungus Streptomyces tsukubaensis. It is a macrolide lactone and acts by inhibiting calcineurin.

It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than cyclosporine and has less pronounced side-effects.

Tacrolimus. Image source: Wikipedia, public domain.

Tacrolimus is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Tacrolimus was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.

Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.

The drug is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506 (Fermentek catalogue number 506). It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation.

Tacrolimus is a macrolide. It binds to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin.

As an ointment (Protopic) tacrolimus and pimecrolimus are used in the treatment of atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy). It may therefore be applied to the thinner skin over the face and eyelids.

Pimecrolimus. Image source: Wikipedia, public domain.

What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?

(A) NFkB
(B) calcium
(C) ipraimmunophilin
(E) calcineurin
(F) calmodulin
(G) AP-1

Answer: E.


Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone. Rapamycin blocks lymphocyte proliferation by inhibiting IL-2 signaling.

Sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island — an island also known as "Rapa Nui", hence the name.

Sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.

Unlike the similarly-named tacrolimus, sirolimus is not a calcineurin inhibitor. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2). In contrast, tacrolimus inhibits the production of IL-2.

Contrary to ciclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation.

The mode of action of Sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway.

Therefore, sirolimus acts synergistically with ciclosporine and, in combination with other immunosuppressants, has few side-effects. Also, it indirectly inhibits several T lymphocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. In a similar manner, it prevents the B cell differentiation to the plasma cells, reducing production of IgM, IgG, and IgA antibodies.

Sirolimus. Image source: Wikipedia, public domain.

A plaque commemorating the discovery of sirolimus on Easter Island, near Rano Kau. Image source: Wikipedia, public domain.


Ciclosporin. Wikipedia.
Tacrolimus. Wikipedia.
Sirolimus. Wikipedia.
Immunosuppressive drugs. Wikipedia.
Abbas' Immunology, edition 6, 2009.

Published: 05/18/2009
Updated: 09/08/2010

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