Faik Imeri, Daniel Fallegger, Aleksandra Zivkovic, Stephanie Schwalm, Gaby Enzmann, Kira Blankenbach, Dagmar Meyer Zu Heringdorf, Thomas Homann, Burkhard Kleuser, Josef Pfeilschifter, Britta Engelhardt, Holger Stark, Andrea Huwiler
- The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P(1) and S1P(3), but not S1P(2), receptor internalization as a result of receptor activation.
Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-mediated downregulation of PECAM-1 mRNA expression.
In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes andThe immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P(1) and S1P(3), but not S1P(2), receptor internalization as a result of receptor activation.
Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-mediated downregulation of PECAM-1 mRNA expression.
In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated.
In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases. (C) 2014 Elsevier Ltd. All rights reserved.…
MetadatenAuthor details: | Faik Imeri, Daniel Fallegger, Aleksandra Zivkovic, Stephanie Schwalm, Gaby Enzmann, Kira Blankenbach, Dagmar Meyer Zu Heringdorf, Thomas HomannORCiD, Burkhard KleuserORCiDGND, Josef Pfeilschifter, Britta Engelhardt, Holger Stark, Andrea Huwiler |
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DOI: | https://doi.org/10.1016/j.neuropharm.2014.05.012 |
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ISSN: | 0028-3908 |
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ISSN: | 1873-7064 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/24863045 |
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Title of parent work (English): | Neuropharmacology |
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Publisher: | Elsevier |
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Place of publishing: | Oxford |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2014 |
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Publication year: | 2014 |
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Release date: | 2017/03/27 |
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Tag: | Endothelial cells; Fingolimod; Multiple sclerosis; Permeability; ST-1071; ST-968; Sphingosine 1-phosphate |
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Volume: | 85 |
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Number of pages: | 14 |
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First page: | 314 |
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Last Page: | 327 |
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Funding institution: | Swiss Society for Multiple Sclerosis; German Research Foundation
[FOG784, SPP1267, HU842/5-1]; Swiss National Science Foundation
[310030-135619] |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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Peer review: | Referiert |
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