(S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity

W.J. Valentine, G.N. Kiss, J. Liu, Shuyu E, M. Gotoh, K. Murakami-Murofushi, T.C. Pham, D.L. Baker, A.L. Parrill, X. Lu, C. Sun, R. Bittman, N.J. Pyne, G. Tigyi

Research output: Contribution to journal › Article

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Abstract

FTY720 (Fingolimod), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P(1) receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P(1) by depleting the functional S1P(1) receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P(1) (EC(50) 20+/-3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P(1,3,4) (K(i) 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P(2), and S1P(5). Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K(i) values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P(2) transcripts and traces of S1P(5). (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.
LanguageEnglish
Pages1543-1553
Number of pages11
JournalCellular Signalling
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 2010

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Immunosuppressive Agents
Lysosphingolipid Receptors
sphingosine 1-phosphate
((E)-3-amino-5-(4-heptylphenyl)-3-(hydroxymethyl)pent-1-enyl)phosphonic acid
Fingolimod Hydrochloride
Camptothecin
Lymphopenia
Multiple Sclerosis
Epithelial Cells
Cell Membrane
Pharmacology
Enzymes

Keywords

  • animals
  • cell line
  • humans
  • lysophospholipids
  • mice
  • phosphodiesterase inhibitors
  • phosphoric acid esters
  • phosphoric diester hydrolases
  • rats
  • receptors
  • signal transduction
  • sphingosine
  • stereoisomerism
  • vinyl compounds

Cite this

Valentine, W.J. ; Kiss, G.N. ; Liu, J. ; E, Shuyu ; Gotoh, M. ; Murakami-Murofushi, K. ; Pham, T.C. ; Baker, D.L. ; Parrill, A.L. ; Lu, X. ; Sun, C. ; Bittman, R. ; Pyne, N.J. ; Tigyi, G. / (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. In: Cellular Signalling. 2010 ; Vol. 22, No. 10. pp. 1543-1553.
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abstract = "FTY720 (Fingolimod), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P(1) receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P(1) by depleting the functional S1P(1) receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P(1) (EC(50) 20+/-3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P(1,3,4) (K(i) 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P(2), and S1P(5). Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K(i) values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P(2) transcripts and traces of S1P(5). (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.",
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author = "W.J. Valentine and G.N. Kiss and J. Liu and Shuyu E and M. Gotoh and K. Murakami-Murofushi and T.C. Pham and D.L. Baker and A.L. Parrill and X. Lu and C. Sun and R. Bittman and N.J. Pyne and G. Tigyi",
note = "Copyright 2010 Elsevier Inc. All rights reserved.",
year = "2010",
month = "10",
doi = "10.1016/j.cellsig.2010.05.023",
language = "English",
volume = "22",
pages = "1543--1553",
journal = "Cellular Signalling",
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Valentine, WJ, Kiss, GN, Liu, J, E, S, Gotoh, M, Murakami-Murofushi, K, Pham, TC, Baker, DL, Parrill, AL, Lu, X, Sun, C, Bittman, R, Pyne, NJ & Tigyi, G 2010, '(S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity' Cellular Signalling, vol. 22, no. 10, pp. 1543-1553. https://doi.org/10.1016/j.cellsig.2010.05.023

(S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. / Valentine, W.J.; Kiss, G.N.; Liu, J.; E, Shuyu ; Gotoh, M.; Murakami-Murofushi, K.; Pham, T.C.; Baker, D.L.; Parrill, A.L.; Lu, X.; Sun, C.; Bittman, R.; Pyne, N.J.; Tigyi, G.

In: Cellular Signalling, Vol. 22, No. 10, 10.2010, p. 1543-1553.

Research output: Contribution to journal › Article

TY - JOUR

T1 - (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity

AU - Valentine, W.J.

AU - Kiss, G.N.

AU - Liu, J.

AU - E, Shuyu

AU - Gotoh, M.

AU - Murakami-Murofushi, K.

AU - Pham, T.C.

AU - Baker, D.L.

AU - Parrill, A.L.

AU - Lu, X.

AU - Sun, C.

AU - Bittman, R.

AU - Pyne, N.J.

AU - Tigyi, G.

N1 - Copyright 2010 Elsevier Inc. All rights reserved.

PY - 2010/10

Y1 - 2010/10

N2 - FTY720 (Fingolimod), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P(1) receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P(1) by depleting the functional S1P(1) receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P(1) (EC(50) 20+/-3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P(1,3,4) (K(i) 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P(2), and S1P(5). Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K(i) values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P(2) transcripts and traces of S1P(5). (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

AB - FTY720 (Fingolimod), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P(1) receptor internalization and targeting to the proteasomal degradative pathway, and thus functions as an antagonist of S1P(1) by depleting the functional S1P(1) receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P(1) (EC(50) 20+/-3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P(1,3,4) (K(i) 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P(2), and S1P(5). Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with K(i) values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P(2) transcripts and traces of S1P(5). (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.

KW - animals

KW - cell line

KW - humans

KW - lysophospholipids

KW - mice

KW - phosphodiesterase inhibitors

KW - phosphoric acid esters

KW - phosphoric diester hydrolases

KW - rats

KW - receptors

KW - signal transduction

KW - sphingosine

KW - stereoisomerism

KW - vinyl compounds

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U2 - 10.1016/j.cellsig.2010.05.023

DO - 10.1016/j.cellsig.2010.05.023

M3 - Article

VL - 22

SP - 1543

EP - 1553

JO - Cellular Signalling

T2 - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

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Valentine WJ, Kiss GN, Liu J, E S, Gotoh M, Murakami-Murofushi K et al. (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. Cellular Signalling. 2010 Oct;22(10):1543-1553. https://doi.org/10.1016/j.cellsig.2010.05.023

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