Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun, Jerold; Giovannoni, Gavin; Hunter, Samuel F.

doi:10.1007/s40265-020-01431-8

Cited by 101 publications

(154 citation statements)

References 132 publications

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“…Indeed, hypertension and ischemia-reperfusion renal injury have been reported with the use of non-selective S1PRs, likely due to S1PR2-S1PR3 modulation. S1PR3 agonism is linked to heart-rate effects and the risk for type I and type II atrioventricular block [ 4 ]. However, despite the lower affinity of new S1P modulators, there are still first-dose cardiac effects, suggesting that S1PR1 plays a role [ 4 ].…”

Section: Sphingosine-1-phosphate (S1p) Signaling In Health and Diseasementioning

confidence: 99%

“…S1PR3 agonism is linked to heart-rate effects and the risk for type I and type II atrioventricular block [ 4 ]. However, despite the lower affinity of new S1P modulators, there are still first-dose cardiac effects, suggesting that S1PR1 plays a role [ 4 ]. In addition, S1PR2 and S1PR3 have been implicated in pathophysiological processes including inflammation, fibrosis, cancer cell growth, and angiogenesis [ 9 ].…”

Section: Sphingosine-1-phosphate (S1p) Signaling In Health and Diseasementioning

confidence: 99%

“…S1PR1 agonists render lymphocytes incapable of sensing the S1P gradient and exiting lymph nodes, preventing their access to circulation and sites of inflammation. More than one mode of action has been proposed, acting as functional antagonists (binding internalizes receptors, desensitizing cells with a net effect of depressing S1PR-mediated signaling) and as traditional agonists (increasing activity through these pathways) [ 2 , 4 , 23 ]. Many S1PR modulators are prodrugs (e.g., fingolimod, amiselimod), which require conversion into their bioactive form by phosphorylation via sphingosine kinases (SphKs), whereas others are direct acting (e.g., ponesimod, siponimod, ozanimod) [ 37 , 38 ].…”

Section: S1pr Agonists/modulators In Immunological Disordersmentioning

confidence: 99%

“…S1PR agonists/modulators or targeting the S1P axis via inhibitors that target S1P generation, transport, and degradation may represent additional “druggable” approaches for the treatment of immune-mediated diseases [ 1 ]. Research on the S1P pathway has led to approval of safe and effective S1PR modulators to treat MS, such as ponesimod, ozanimod, siponimod, and fingolimod [ 4 ]. Several other agents are in clinical development for MS, including amiselimod, cerafilimod, etrasimod, and GSK2018682 [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Research on the S1P pathway has led to approval of safe and effective S1PR modulators to treat MS, such as ponesimod, ozanimod, siponimod, and fingolimod [ 4 ]. Several other agents are in clinical development for MS, including amiselimod, cerafilimod, etrasimod, and GSK2018682 [ 4 ]. Beyond MS, therapies targeting S1P pathways have expanded to treat other inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Pérez-Jeldres

Álvarez-Lobos

Rivera–Nieves

2021

Drugs

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Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

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Section: Sphingosine-1-phosphate (S1p) Signaling In Health and Diseasementioning

confidence: 99%

Section: Sphingosine-1-phosphate (S1p) Signaling In Health and Diseasementioning

confidence: 99%

Section: S1pr Agonists/modulators In Immunological Disordersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Pérez-Jeldres

Álvarez-Lobos

Rivera–Nieves

2021

Drugs

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Sphingosine 1‐phosphate receptor modulators in multiple sclerosis treatment: A practical review

Coyle,

Freedman,

Cohen

et al. 2024

Ann Clin Transl Neurol

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Four sphingosine 1‐phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head‐to‐head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real‐world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

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Structural determinants of sphingosine‐1‐phosphate receptor selectivity

Wunsch,

Nguyen,

Wolber

et al. 2023

Archiv der Pharmazie

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Fingolimod, the prodrug of fingolimod‐1‐phosphate (F1P), was the first sphingosine‐1‐phosphate receptor (S1PR) modulator approved for multiple sclerosis. F1P unselectively targets all five S1PR subtypes. While agonism (functional antagonism via receptor internalization) at S1PR1 leads to the desired immune modulatory effects, agonism at S1PR3 is associated with cardiac adverse effects. This motivated the development of S1PR3‐sparing compounds and led to a second generation of S1PR1,5‐selective ligands like siponimod and ozanimod. Our method combines molecular dynamics simulations and three‐dimensional pharmacophores (dynophores) and enables the elucidation of S1PR subtype‐specific binding site characteristics, visualizing also subtle differences in receptor–ligand interactions. F1P and the endogenous ligand sphingosine‐1‐phosphate bind to the orthosteric pocket of all S1PRs, but show different binding mode dynamics, uncovering potential starting points for the development of subtype‐specific ligands. Our study contributes to the mechanistic understanding of the selectivity profile of approved drugs like ozanimod and siponimod and pharmaceutical tool compounds like CYM5541.

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Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Cited by 101 publications

References 132 publications

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Sphingosine 1‐phosphate receptor modulators in multiple sclerosis treatment: A practical review

Structural determinants of sphingosine‐1‐phosphate receptor selectivity

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