Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 107

calcium ions that regularly bind to calcineurin after activation of the T-cell
receptor.Subsequent to the inhibition ofcalcineurin activation,the signal trans-
duction leading to the transcription of gene encoding,e.g.for interleukin-2,is
prevented.As a consequence,T-cell proliferation does not occur.However,the
rapamycin/FKBP complex does not bind to calcineurin,but inactivates protein
kinases that respond to interleukin-2 receptor activation by stimulating T-cell
proliferation. Cyclosporin A was shown to bind to another type of immuno-
philin called cyclophilin. Surprisingly, the cyclosporin A/cyclophilin complex
binds to calcineurin at the same site as FK 506/FKBP does, thus eventually
triggering the same steps of the cell signaling cascade [31].
Although, at the time of discovery FK 506 was reported as a new immuno-
suppressant agent being 100-fold more potent than cyclosporin A,efforts to dis-
place cyclosporin A by FK 506,commercialized as tacrolimus,failed until today.
It is worth mentioning that FK 506 stimulated the setup of the venture capital
funded US company Vertex that aims at a designed drug to treat HIV infections
starting from FK 506 as a lead compound.
FK 506
cyclosporin A
rapamycin
Fig. 1. Immunosuppressive agents cyclosporin A,FK 506,and rapamycin