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sirolimus

Friday 27 March 2009

Definition: Sirolimus (INN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants (WKP).

A macrolide, 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.

It is marketed under the trade name Rapamune by Wyeth.

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

Action

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) and thereby blocks activation of T- and B-cells. In contrast, tacrolimus inhibits the production of IL-2.

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 by directly binding the mTOR Complex1 (mTORC1).

Nomenclature

mTOR is also called FRAP (FKBP-rapamycin associated protein) or RAFT (rapamycin and FKBP target). FRAP and RAFT are actually more accurate names since they reflect the fact that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin complex can bind FRAP/RAFT/mTOR.

See also

- WKP