siponimod and sphingosine-1-phosphate

The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P

Topics: Dose-Response Relationship, Drug; Fingolimod Hydrochloride; Humans; Ligands; Lysophospholipids; Molecular Structure; Receptors, Lysosphingolipid; Sphingosine; Structure-Activity Relationship

Allogeneic haemopoietic stem cell transplantation (HSCT) is increasingly used to treat haematological malignant diseases via the graft-versus-leukaemia (GvL) or graft-versus-tumour effects. Although improvements in infectious disease prophylaxis, immunosuppressive treatments, supportive care, and molecular based tissue typing have contributed to enhanced outcomes, acute graft-versus-host disease and other transplant related complications still contribute to high mortality and significantly limit the more widespread use of HSCT. Sphingosine 1-phosphate (S1P) is a zwitterionic lysophospholipid that has been implicated as a crucial signaling regulator in many physiological and pathophysiological processes including multiple cell types such as macrophages, dendritic cells, T cells, T regulatory cells and endothelial cells. Recent data suggested important roles for S1P signaling in engraftment, graft-versus-host disease (GvHD), GvL and other processes that occur during and after HSCT. Based on such data, pharmacological intervention via S1P modulation may have the potential to improve patient outcome by regulating GvHD and enhancing engraftment while permitting effective GvL.

Topics: Azetidines; Benzyl Compounds; Dendritic Cells; Endothelial Cells; Graft vs Host Disease; Graft vs Leukemia Effect; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lysophospholipids; Macrophages; Organophosphates; Protein Isoforms; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; T-Lymphocytes, Regulatory; Transplantation, Homologous

Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR-G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P

Topics: Animals; Azetidines; Benzyl Compounds; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Lysophospholipids; Molecular Conformation; Molecular Docking Simulation; Multiple Sclerosis; Receptors, Lysophosphatidic Acid; Recombinant Proteins; Sf9 Cells; Single Molecule Imaging; Sphingosine; Sphingosine-1-Phosphate Receptors; Spodoptera

The Siponimod (Mayzent) is a newly developed drug, similar to Fingolimod (FTY720) but with fewer side effects, approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS). The therapeutic effect of siponimod and FTY720 in MS relies on their inhibitory effect on the sphingosine 1-phosphate (S1P) signaling. These drugs bind to the S1P receptors and block the CCL2 chemokine pathway that is responsible for the exit of the immune cells from the lymphoid organs, and circulation, thus preventing immune cell-dependent injury to the nervous system. We recently found that FTY720 beside its effect on the S1P pathway also blocks the RhoA pathway, which is involved in the actin cytoskeleton-related function of macrophages, such as expression/recycling of fractalkine (CX3CL1) receptors (CX3CR1), which direct macrophages to the transplanted organs during the development of the long-term (chronic) rejection. Here we tested the effects of siponimod on the RhoA pathway and the expression of the S1P1 and CX3CR1 receptors in mouse RAW 264.7 macrophages. We found that siponimod downregulates the expression of RhoA protein and decreases the cell surface expression of S1P1 and CX3CR1 receptors. This newly discovered crosstalk between S1P and RhoA/CX3CR1 pathways may help in the development of novel anti-chronic rejection therapies in clinical transplantation.

Topics: Actin Cytoskeleton; Animals; Azetidines; Benzyl Compounds; Cell Membrane; Chemokine CCL2; Down-Regulation; Fingolimod Hydrochloride; Graft Rejection; Humans; Lysophospholipids; Macrophages; Membrane Proteins; Mice; Multiple Sclerosis; Organ Transplantation; Phosphoric Monoester Hydrolases; RAW 264.7 Cells; Receptors, Interleukin-8A; rhoA GTP-Binding Protein; Signal Transduction; Sphingosine; United States; United States Food and Drug Administration