Sirolimus and tacrolimus are macrolide compounds obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. They are bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, peptidyl-prolyl cis-trans isomerase (FKBP1A, FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP1A complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.
Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP1A, creating a new complex. This complex inhibits calcineurin which inhibits T-lymphocyte signal transduction and IL-2 transcription (Kino et al. 1987, Ding et al. 2019).