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.