Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P<sub>1</sub>) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO)...
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MDPI AG
2012-05-01
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| Series: | Pharmaceuticals |
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| Online Access: | http://www.mdpi.com/1424-8247/5/5/514 |
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| author | Kunitomo Adachi Kenji Chiba |
| author_facet | Kunitomo Adachi Kenji Chiba |
| author_sort | Kunitomo Adachi |
| collection | DOAJ |
| description | Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P<sub>1</sub>) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P<sub>1</sub>. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P<sub>1</sub>, S1P<sub>3</sub>, S1P<sub>4</sub>, and S1P<sub>5</sub>). In particular, FTY720-P strongly induces internalization and degradation of S1P<sub>1</sub>, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P<sub>1</sub>. Consequently, FTY720 inhibits S1P<sub>1</sub>-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex<sup>®</sup>), S1P<sub>1</sub> is presumed to be a useful target for the therapy of MS. |
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| language | English |
| last_indexed | 2024-12-19T05:44:30Z |
| publishDate | 2012-05-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-6744b1ae8eed414d825ce7753c347a602022-12-21T20:33:53ZengMDPI AGPharmaceuticals1424-82472012-05-015551452810.3390/ph5050514Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple SclerosisKunitomo AdachiKenji ChibaSphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P<sub>1</sub>) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P<sub>1</sub>. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P<sub>1</sub>, S1P<sub>3</sub>, S1P<sub>4</sub>, and S1P<sub>5</sub>). In particular, FTY720-P strongly induces internalization and degradation of S1P<sub>1</sub>, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P<sub>1</sub>. Consequently, FTY720 inhibits S1P<sub>1</sub>-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex<sup>®</sup>), S1P<sub>1</sub> is presumed to be a useful target for the therapy of MS.http://www.mdpi.com/1424-8247/5/5/514sphingosine 1-phasphate (S1P)S1P receptor 1 (S1P<sub>1</sub>)fingolimod (FTY720)lymphocyte egressimmunomodulatorexperimental autoimmune encephalomyelitis (EAE)multiple sclerosis (MS)therapy |
| spellingShingle | Kunitomo Adachi Kenji Chiba Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis Pharmaceuticals sphingosine 1-phasphate (S1P) S1P receptor 1 (S1P<sub>1</sub>) fingolimod (FTY720) lymphocyte egress immunomodulator experimental autoimmune encephalomyelitis (EAE) multiple sclerosis (MS) therapy |
| title | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
| title_full | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
| title_fullStr | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
| title_full_unstemmed | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
| title_short | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
| title_sort | sphingosine 1 phosphate receptor 1 as a useful target for treatment of multiple sclerosis |
| topic | sphingosine 1-phasphate (S1P) S1P receptor 1 (S1P<sub>1</sub>) fingolimod (FTY720) lymphocyte egress immunomodulator experimental autoimmune encephalomyelitis (EAE) multiple sclerosis (MS) therapy |
| url | http://www.mdpi.com/1424-8247/5/5/514 |
| work_keys_str_mv | AT kunitomoadachi sphingosine1phosphatereceptor1asausefultargetfortreatmentofmultiplesclerosis AT kenjichiba sphingosine1phosphatereceptor1asausefultargetfortreatmentofmultiplesclerosis |