guanosine-triphosphate and Lymphopenia

Topics: Adult; B-Lymphocytes; Disease Progression; Gain of Function Mutation; Graft vs Host Disease; GTPase-Activating Proteins; Guanosine Triphosphate; Hematopoietic Stem Cell Transplantation; Heterozygote; Humans; Immunologic Memory; Immunosuppressive Agents; Infant; Lung Diseases; Lung Transplantation; Lymphopenia; Male; Molecular Docking Simulation; Neutrophils; Primary Immunodeficiency Diseases; rac GTP-Binding Proteins; RAC2 GTP-Binding Protein; Recurrence; Respiratory Tract Infections; T-Lymphocyte Subsets; T-Lymphocytes

The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P(1-5)). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P(1) and S1P(3) receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.

Topics: Animals; Capillary Permeability; Cell Line; Guanosine Triphosphate; Indicators and Reagents; Lymphopenia; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Molecular Conformation; Optical Rotation; Organophosphonates; Receptors, Lysosphingolipid; Tissue Distribution