Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm.
New insights have been gained into the therapeutic relevance of the sphingosine 1-phosphate (S1P) pathway, on the basis of reverse pharmacological approaches to defining the mechanism of action of the immunosuppressive agent FTY720. Natural and synthetic sphingosine 1-phosphate receptor agonists can make picomolar interactions with their cognate G-protein-coupled receptors, and provide chemical approaches to defining the contribution of distinct receptor subtypes to pathology, physiology and treatment. The chemistry of S1P receptors and their synthetic ligands present a paradigm for the understanding of lipid-receptor interactions and their contribution to physiology and pathology. These approaches can potentially be extended to a broad, related family of G-protein-coupled receptors that share ligands and ligand similarities.
Rosen
Hugh
H
Department of Immunology and Committee for Advanced Human Therapeutics, The Scripps Research Institute, ICND-118 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. hrosen@scripps.edu
Liao
Jiayu
J
D000818:Animals; D001667:Binding, Competitive; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008024:Ligands; D008214:Lymphocytes / Q000276:immunology; D008246:Lysophospholipids; D011409:Propylene Glycols / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D049312:Receptors, Lysophospholipid; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D008024:Ligands; D008246:Lysophospholipids; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine