Fine-tuning S1P therapeutics

Abstract

Sphingosine 1-phosphate receptor-1 (S1P(1)), a novel therapeutic target for multiple sclerosis, regulates lymphocyte trafficking, heart rate, and vascular function. The discovery of NIBR-0213, a competitive antagonist for S1P(1) that inhibits autoimmune inflammation while sparing bradycardia (Quancard et al., in this issue of Chemistry & Biology), suggests that fine-tuning of S1P(1) modulators may lead to novel immune modulators with better efficacy to adverse events ratio.

Figure 1. Signaling Systems for Natural Ligand, Functional Antagonist, and Competitive Antagonist

(A) S1P activates S1P₁ and regulates vascular permeability in endothelial cells and lymphocyte egress from secondary lymphoid organs. S1P₁ is recycled back to the cell surface after S1P-induced internalization. (B) FTY720-P induces ubiquitin-dependent degradation of S1P₁, resulting in functional antagonism, which induces increased vascular permeability and lymphopenia. The agonistic effects of FTY720-P on S1P₁, on the other hand, activate the GIRK channel on cardiomyocytes, leading to bradycardia. (C) NIBR-0213 competitively antagonizes S1P₁, which also induces increased vascular permeability and lymphopenia while sparing bradycardia.