Sphingosine 1-phosphate (SIP) is a pleiotropic lipid mediator that is most commonly associated with cell migration, cell survival and vasculogenesis. The recent discovery that the novel sphingosine-like drug, FTY720, is a pro-drug that after phosphorylation targets S1P receptors provides a fascinating insight into S1P biology. FTY720 treatment sequesters lymphocytes in secondary lymphoid tissue and away from inflamed peripheral tissues and graft sites. The drug is protective in both allogenic transplant and autoimmune disease models and was found to be safe and effective in a human renal transplantation trial. Importantly, FTY720-treated animals are resistant to systemic viral infection; if confirmed in humans, this represents a striking advantage over existing immunosuppressive therapeutic regimens. However, the precise molecular targets - the activating kinase, the S1P receptor types and the inactivating phosphatase - remain undefined. Further, FTY720 is not without problems, i.e. about 30% of patients experience a transient, asymptomatic bradycardia with onset of therapy. Thus our present Aims can be stated succinctly as: (1) synthesize sphingosine-like and S1P-like compounds that mimic the FTY720- evoked lymphopenia due to lymphocyte sequestration, (2) characterize these new chemical entities regarding activity at individual S1P receptors and metabolic enzymes and (3) discover the kinase that activates FTY720 and like compounds by phosphorylation. The strength of our program is the combination of synthetic chemistry and molecular pharmacology - an interaction strengthened by the molecular definition of target proteins including the S1P receptors and S1P phosphohydrolases. Minimally, our efforts will extend significantly knowledge of the structure activity relationships (SAR) for S1P receptors, phosphatases and lipid kinases. Optimally, we will discover new FTY720-1ike entities with enhanced selectivity and lessened toxicity and we will discover additional lipid kinases. Our work will also lead to the discovery of S1P receptor selective antagonists and agonists - indeed we have already found several such compounds. These agents will enable a determination of the effects of blockage or mimicry of S1P signaling and thus provide crucial information as to what additional S1P signaling pathways might be valid targets for therapeutic intervention. ? ?
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