- Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced aMultiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced a profound lymphopenia in mice. Finally, these substances showed efficacy in the EAE model, where they reduced clinical symptoms of the disease, and, on the molecular level, they reduced the T-cell infiltration and several inflammatory mediators in the brain and spinal cord. In summary, these data suggest that S1P(1)-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.…
MetadatenAuthor details: | Bisera StepanovskaGND, Aleksandra Zivkovic, Gaby Enzmann, Silvia Tietz, Thomas Homann, Burkhard KleuserORCiDGND, Britta EngelhardtORCiDGND, Holger StarkORCiD, Andrea HuwilerORCiDGND |
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DOI: | https://doi.org/10.3390/ijms21186463 |
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ISSN: | 1422-0067 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/32899717 |
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Title of parent work (English): | International journal of molecular sciences |
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Publisher: | MDPI |
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Place of publishing: | Basel |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2020/09/04 |
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Publication year: | 2020 |
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Release date: | 2024/01/11 |
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Tag: | 1-phosphate; ST-1893; ST-1894; experimental antigen-induced encephalomyelitis; immunomodulator; lymphopenia; morpholino analogues of fingolimod; multiple sclerosis; sphingosine |
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Volume: | 21 |
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Issue: | 18 |
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Article number: | 6463 |
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Number of pages: | 17 |
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Funding institution: | Swiss Society for Multiple Sclerosis; Swiss National Science; FoundationSwiss National Science Foundation (SNSF)European Commission; [310030_135619]; German Research FoundationGerman Research Foundation; (DFG) [GRK2158, INST 208/690-1]; EU-COST Actions [CA15135, CA18240] |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
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| 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Peer review: | Referiert |
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Publishing method: | Open Access / Gold Open-Access |
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| DOAJ gelistet |
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License (German): | CC-BY - Namensnennung 4.0 International |
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