FTY720 is sphingosine-1-phosphate (S1P) receptors agonist [1]. FTY720 is a novel immunomodulatory agent derived from ISP-1 (myriocin), a fungal metabolite that exists in traditional Chinese herbal medicine. In higher eukaryotes, S1P is the ligand for five G-protein-coupled receptors. These S1P receptors are differentially expressed and regulate vascular maturation, angiogenesis, cardiac development and immunity. S1P receptors are important for directed cell movement [2].
In vitro: The phosphorylated FTY720 acted as agonist for a family of G protein-coupled receptors in vitro. FTY720 inhibited sphingosine-1-phosphate lyase activity [3]. FTY720 phosphate acted as a potent agonist at sphingosine-1-phosphate (S1P) receptors S1P1, S1P3, S1P4, and S1P5 with IC50 values of 0.2-6 nM [3].
In vivo: In a variety of transplant and autoimmune models, FTY720 was efficacious without inducing a generalized immunosuppressed state. FTY720 was effective in human kidney transplantation. FTY720 elicited lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. In a rodent model of multiple sclerosis, the phosphorylated FTY720 compound was a potent agonist at four s S1P receptors. Phosphorylation of FTY720 acted through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking [1]. FTY720 was phosphorylated in vivo. In mice, treatment with FTY720 inhibited tissue sphingosine-1-phosphate lyase activity, whereas lyase gene and protein expression were not significantly affected [3].
References:
[1] Brinkmann V, Davis M D, Heise C E, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors[J]. Journal of Biological Chemistry, 2002, 277(24): 21453-21457.
[2] Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid[J]. Nature reviews Molecular cell biology, 2003, 4(5): 397-407.
[3] Bandhuvula P, Tam Y Y, Oskouian B, et al. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity[J]. Journal of Biological Chemistry, 2005, 280(40): 33697-33700.