Sirolimus: its discovery, biological properties, and mechanism of action.

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Sehgal SN

Sirolimus: its discovery, biological properties, and mechanism of action.

Transplant Proc. 2003 May;35(3 Suppl):7S-14S.

PubMed ID

12742462 [ View in PubMed

]

Abstract

Sirolimus is the USAN-assigned generic name for the natural product rapamycin. Sirolimus is produced by a strain of Streptomyces hygroscopicus, isolated from a soil sample collected from Rapa Nui commonly known as Easter Island. Although sirolimus was isolated as an antifungal agent with potent anticandida activity, subsequent studies revealed impressive antitumor and immunosuppressive activities. Sirolimus demonstrates activity against several murine tumors, such as B16 43 melanocarcinoma, Colon 26 tumor, EM ependymoblastoma, and mammary and colon 38 solid tumors. Sirolimus is a potent inhibitor of antigen-induced proliferation of T cells, B cells, and antibody production. Demonstration of the potent immunosuppressive activity of sirolimus in animal models of organ transplantation led to clinical trials and subsequent approval by regulatory authorities for prophylaxis of renal graft rejection. Interest in sirolimus as an immunosuppressive therapy in organ transplantation derives from its unique mechanism of action, its unique side-effect profile, and its ability to synergize with other immunosuppressive agents. The molecular mechanism underlying the antifungal, antiproliferative, and immunosuppressive activities of sirolimus is the same. Sirolimus forms an immunosuppressive complex with intracellular protein, FKBP12. This complex blocks the activation of the cell-cycle-specific kinase, TOR. The downstream events that follow the inactivation of TOR result in the blockage of cell-cycle progression at the juncture of G1 and S phase.

DrugBank Data that Cites this Article

Drugs

Sirolimus

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sirolimus	Serine/threonine-protein kinase mTOR	Protein	Humans	Yes	Inhibitor	Details