Morpholino Analogues of Fingolimod as Novel and Selective S1P1 Ligands with In Vivo Efficacy in a Mouse Model of Experimental Antigen-Induced Encephalomyelitis.

Stepanovska, Bisera; Zivkovic, Aleksandra; Enzmann, Gaby; Tietz, Silvia; Homann, Thomas; Kleuser, Burkhard; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea (2020). Morpholino Analogues of Fingolimod as Novel and Selective S1P1 Ligands with In Vivo Efficacy in a Mouse Model of Experimental Antigen-Induced Encephalomyelitis. International journal of molecular sciences, 21(18), pp. 1-17. MDPI 10.3390/ijms21186463

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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®), which acts as a functional S1P1 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 S1P1 activation profile and a sustained S1P1 internalization in cultures of S1P1-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 S1P1-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Stepanovska, Bisera; Enzmann, Gaby; Tietz, Silvia Martina; Engelhardt, Britta and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1422-0067

Publisher:

MDPI

Language:

English

Submitter:

Celine Joray

Date Deposited:

23 Sep 2020 10:49

Last Modified:

23 Sep 2020 10:49

Publisher DOI:

10.3390/ijms21186463

PubMed ID:

32899717

Uncontrolled Keywords:

ST-1893 ST-1894 experimental antigen-induced encephalomyelitis immunomodulator lymphopenia morpholino analogues of fingolimod multiple sclerosis sphingosine 1-phosphate

BORIS DOI:

10.7892/boris.146664

URI:

https://boris.unibe.ch/id/eprint/146664

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