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Selectivity and specificity of sphingosine 1-phosphate receptor ligands: "off-targets" or complex pharmacology?

Pyne NJ, Pyne S - Front Pharmacol (2011)

Bottom Line: This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects.Therefore the perspective cautioned against the use of these S1P receptor ligands.Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, UK.

ABSTRACT
A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects.

No MeSH data available.


(A) Phosphorylation of FTY720 by sphingosine kinase 2 (SK2) and release to induce down-regulation of S1P1. (B) and (C) Equilibrium transition model showing the binding of S1P, FTY720 phosphate (FTY720P), or VPC23019 (VPC) to the conformational states (denoted by different shapes) of S1P3 coupled to different G-proteins. The positions of the equilibrium in (B,C) will be affected by binding of S1P, FTY720P, or VPC23019 to the different conformations of S1P3 but are not represented here for simplicity. The ligands are shown in red.
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Figure 1: (A) Phosphorylation of FTY720 by sphingosine kinase 2 (SK2) and release to induce down-regulation of S1P1. (B) and (C) Equilibrium transition model showing the binding of S1P, FTY720 phosphate (FTY720P), or VPC23019 (VPC) to the conformational states (denoted by different shapes) of S1P3 coupled to different G-proteins. The positions of the equilibrium in (B,C) will be affected by binding of S1P, FTY720P, or VPC23019 to the different conformations of S1P3 but are not represented here for simplicity. The ligands are shown in red.

Mentions: FTY720 (or fingolimod) is an immunosuppressant that was very recently licensed by the Food and Drug Administration and the European Medicines Agency as Gilenya™. This sphingosine analog is taken up by cells, phosphorylated by sphingosine kinase 2 (SK2) and released as FTY720 phosphate. FTY720 phosphate binds to and activates S1P1, S1P3, S1P4, and S1P5, but not S1P2 (Brinkmann et al., 2010). FTY720 phosphate also induces a later “functional antagonism” by promoting the polyubiquitination, endocytosis, and proteasomal degradation of S1P1 (Gräler and Goetzl, 2004), which creates S1P1 receptor T-cells to induce lymphopenia. In contrast, S1P1 receptors recycle in response to S1P. Therefore, S1P and FTY720 phosphate do not appear to bind to and stabilize the same conformation of S1P1. These different conformational states are likely to exist in equilibrium, as binding of FTY720 phosphate to a specific S1P1 conformation will increase its concentration by mass action such that the entire population of S1P1 will be eventually degraded in response to FTY720 phosphate, and this is indeed the case (Figure 1A).


Selectivity and specificity of sphingosine 1-phosphate receptor ligands: "off-targets" or complex pharmacology?

Pyne NJ, Pyne S - Front Pharmacol (2011)

(A) Phosphorylation of FTY720 by sphingosine kinase 2 (SK2) and release to induce down-regulation of S1P1. (B) and (C) Equilibrium transition model showing the binding of S1P, FTY720 phosphate (FTY720P), or VPC23019 (VPC) to the conformational states (denoted by different shapes) of S1P3 coupled to different G-proteins. The positions of the equilibrium in (B,C) will be affected by binding of S1P, FTY720P, or VPC23019 to the different conformations of S1P3 but are not represented here for simplicity. The ligands are shown in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108476&req=5

Figure 1: (A) Phosphorylation of FTY720 by sphingosine kinase 2 (SK2) and release to induce down-regulation of S1P1. (B) and (C) Equilibrium transition model showing the binding of S1P, FTY720 phosphate (FTY720P), or VPC23019 (VPC) to the conformational states (denoted by different shapes) of S1P3 coupled to different G-proteins. The positions of the equilibrium in (B,C) will be affected by binding of S1P, FTY720P, or VPC23019 to the different conformations of S1P3 but are not represented here for simplicity. The ligands are shown in red.
Mentions: FTY720 (or fingolimod) is an immunosuppressant that was very recently licensed by the Food and Drug Administration and the European Medicines Agency as Gilenya™. This sphingosine analog is taken up by cells, phosphorylated by sphingosine kinase 2 (SK2) and released as FTY720 phosphate. FTY720 phosphate binds to and activates S1P1, S1P3, S1P4, and S1P5, but not S1P2 (Brinkmann et al., 2010). FTY720 phosphate also induces a later “functional antagonism” by promoting the polyubiquitination, endocytosis, and proteasomal degradation of S1P1 (Gräler and Goetzl, 2004), which creates S1P1 receptor T-cells to induce lymphopenia. In contrast, S1P1 receptors recycle in response to S1P. Therefore, S1P and FTY720 phosphate do not appear to bind to and stabilize the same conformation of S1P1. These different conformational states are likely to exist in equilibrium, as binding of FTY720 phosphate to a specific S1P1 conformation will increase its concentration by mass action such that the entire population of S1P1 will be eventually degraded in response to FTY720 phosphate, and this is indeed the case (Figure 1A).

Bottom Line: This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects.Therefore the perspective cautioned against the use of these S1P receptor ligands.Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, UK.

ABSTRACT
A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects.

No MeSH data available.