Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects
TLDR
The S1P pathway, the characteristics and S1PR binding profiles of S1 PR modulators, the mechanisms of action of S2PR modulators with regard to immune cell trafficking and neuroprotection in MS are reviewed, together with a summary of the clinical effectiveness of the S1pr modulators that are approved or in late-stage development for patients with MS.Abstract:
Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR1 to S1PR5. Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb).read more
Citations
More filters
Journal ArticleDOI
Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis.
TL;DR: The S1P-S1PR pathway is involved in the pathogenesis of several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking as discussed by the authors.
Journal ArticleDOI
Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies.
TL;DR: This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.
Journal ArticleDOI
Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Shian Liu,Navid Paknejad,Lan Zhu,Yasuki Kihara,Manisha Ray,Jerold Chun,Wei Liu,Richard K Hite,Xin-Yun Huang +8 more
TL;DR: In this article , single-particle cryo-EM structures of human S1P receptor 1 (S1P 1 ) and heterotrimeric G i complexes formed with bound s1P or the multiple sclerosis treatment drug Siponimod, as well as human lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S 1P) complexes in the presence of LPA were reported.
Journal ArticleDOI
Sphingolipids as Modulators of SARS-CoV-2 Infection
Kid Törnquist,Kid Törnquist,Muhammad Yasir Asghar,Vignesh Srinivasan,Vignesh Srinivasan,Laura Korhonen,Dan Lindholm,Dan Lindholm +7 more
TL;DR: In this article, the authors reviewed recent findings regarding sphingolipids in the uptake of SARS-CoV-2 and in the course of COVID-19 disease.
Journal ArticleDOI
Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid.
TL;DR: A review of LysoPS-specific G protein-coupled receptors (GPCRs) can be found in this paper, where four GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs.
References
More filters
Journal ArticleDOI
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
Mehrdad Matloubian,Charles G. Lo,Guy Cinamon,Matthew J. Lesneski,Ying Xu,Volker Brinkmann,Maria L. Allende,Richard L. Proia,Jason G. Cyster +8 more
TL;DR: It is established that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
Journal ArticleDOI
A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Ludwig Kappos,Ernst Wilhelm Radue,Paul O'Connor,Chris H. Polman,Reinhard Hohlfeld,Peter A. Calabresi,Krzysztof Selmaj,Catherine Agoropoulou,Malgorzata Leyk,Lixin Zhang-Auberson,Pascale Burtin +10 more
TL;DR: Both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI and were superior to placebo with regard to MRI-related measures.
Journal ArticleDOI
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
Jeffrey A. Cohen,Frederik Barkhof,Giancarlo Comi,Hans Peter Hartung,Bhupendra Khatri,Xavier Montalban,Jean Pelletier,Ruggero Capra,Paolo Gallo,Guillermo Izquierdo,Klaus Tiel-Wilck,Ana de Vera,James Jin,Tracy Stites,Stacy Wu,Shreeram Aradhye,Ludwig Kappos +16 more
TL;DR: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.
Journal ArticleDOI
Sphingosine-1-phosphate: an enigmatic signalling lipid
Sarah Spiegel,Sheldon Milstien +1 more
TL;DR: The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions.
Journal ArticleDOI
The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
Volker Brinkmann,Michael Davis,Christopher E. Heise,R. Albert,Sylvain Cottens,Robert Paul Hof,Christian Bruns,Eva Prieschl,Thomas Baumruker,Peter Hiestand,Carolyn An Foster,Markus Zollinger,Kevin R. Lynch +12 more
TL;DR: The results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.